TW202146385A - Substituted pyrrolidine compound and use thereof in medicine - Google Patents

Abstract

Disclosed are a substituted pyrrolidine compound and the use thereof in medicine. In particular, disclosed are a substituted pyrrolidine compound or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutical composition containing the above-mentioned compound. Also disclosed is the use of the above-mentioned compound or the pharmaceutical composition thereof in the preparation of a drug, the drug being used to treat PDE4-related diseases, such as atopic dermatitis (AD) or chronic obstructive pulmonary disease (COPD).

Description

Substituted pyrrolidine compounds and their application in medicine

The present invention belongs to the field of medicine, and particularly relates to a class of substituted pyrrolidine compounds, pharmaceutical compositions comprising the compounds, and uses and methods of use thereof. In particular, the compounds described in the present invention are PDE4 inhibitors for the treatment of PDE4-related diseases such as atopic dermatitis (AD), psoriasis or chronic obstructive pulmonary disease (COPD).

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

Phosphodiesterases (PDEs) have been reported to date with 11 gene families, each of which includes multiple subfamilies. PDEs are distributed in multiple tissues, and their inhibitors have a wide range of physiological effects. Among them, PDE4, PDE7 and PDE8 mainly specifically hydrolyze cAMP, PDE5, PDE6 and PDE9 specifically hydrolyze cGMP, while PDE1, PDE2, PDE3, PDE10 and PDE11 It works 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, and its inhibitors can be used to treat various diseases, including allergic and inflammatory diseases, diabetes, central nervous system diseases and pain.

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

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

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

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

Specifically:

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

(I);

in:

X is CH or N;

Y is -(CH ₂ ) _m -C(=O)-NH-(CR ^m R ⁿ ) _p - or -(CH ₂ ) _m -C(=O)-O-(CR ^m R ⁿ ) _p -;

Ring A is a C _6-10 aryl group or a heteroaryl group consisting of 5-10 atoms;

R ¹ is hydrogen, deuterium, -OR ^a or -NR ^c R ^d ;

R ² is C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl, a hetero group consisting of 5-7 atoms Cyclic or (heterocyclyl consisting of 5-7 atoms)-C _1-4 alkyl; or

R ² and R ^a and the connected atoms together form a heterocyclic group composed of 5-7 atoms, and the heterocyclic group composed of 5-7 atoms is optionally selected from deuterium, F, Cl, Br, Substituted by substituents of I, -OH, -CN, -NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or halogenated C _{1-4 alkyl;}

R ³ is hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl-C(=O)-, HC(=O)-, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-S(=O) ₂ - or C _1-6 alkyl-C(=NH)-, wherein said C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl -C (= O) -, C 1 _-6Alkyl -OC(=O)-, _C1-6Alkyl -S(=O) _2- and _C1-6Alkyl -C(=NH)- are each independently optionally replaced by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN or -NH ₂ are substituted;

^{R 4, R 5a, R 5b} , R 6, R 7a, R 7b, R 8 and R ⁹ are each independently hydrogen, deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, - NO ₂ , -COOH, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, C _1-4 alkyl-C(=O)- or C _1-4 alkyl -S(=O) _2- ;

R ^a is hydrogen, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, heterocyclic group consisting of 5-10 atoms, C _{6- 10} aryl groups or heteroaryl groups composed of 5-10 atoms, wherein the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 cycloalkyl group, 5 - Heterocyclyl of 10 atoms, C _6-10 aryl and heteroaryl of 5-10 atoms are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br , I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or composed of 5-10 atoms Substituted by substituents of heterocyclyl;

Each R ^{b is} independently deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, oxo, C _1-6 alkyl, C _1-6 alkoxy , C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O) _2- , C _3-8 cycloalkane Base-C _1-6 alkyl, C _3-8 cycloalkyl, heterocyclic group composed of 5-10 atoms, C _6-10 aryl group, heteroaryl group composed of 5-10 atoms, -NR ^e C (=O)C _1-6 alkyl, -NR ^e R ^f , -S(=O) ₂ -NR ^e R ^f , -C(=O)-NR ^e R ^f or -C _1-6 alkyl- NR ^e R ^f , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl-C _1-6 alkyl, C _3-8 cycloalkyl, 5- Heterocyclyl of 10 atoms, C _6-10 aryl and heteroaryl of 5-10 atoms are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkylamino or C _1-6 alkoxy substituent;

R ^c and R ^d are each independently hydrogen, -OH, C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl-C _1-4 alkyl, C _3-6 cyclo Alkyl, heterocyclyl of 5-7 atoms, (heterocyclyl of 5-7 atoms)-C _1-4 alkyl, C _1-4 alkyl-C(=O)- or C _{1 -4} alkyl-S(=O) ₂ -;

R ^e and R ^f are each independently hydrogen, C _1-6 alkyl, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, C _{1-6 alkyl} Alkyl-S(=O) ₂ -, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 atoms of heterocyclyl, 5-10 atoms of heteroaryl, 11- Heteroaryl consisting of 15 atoms, C _3-8 cycloalkyl-C _1-6 alkyl, C _6-10 aryl-C _1-6 alkyl, (heterocyclic group consisting of 5-10 atoms) -C _1-6 alkyl, (heteroaryl consisting of 5-10 atoms)-C _1-6 alkyl or -C _1-6 alkyl-NR ^g R ^j ; or R ^e and R ^f are attached to them The N atoms together form a heterocyclic group consisting of 4-7 atoms; wherein, the R ^e , R ^f and the heterocyclic group consisting of 4-7 atoms are each independently optionally replaced by 1, 2, 3 or 4 replaced by R ^h;

Each R ^h is independently deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, C 1-4 alkyl, C _{1-4 haloalkyl,} C _{1-4 haloalkoxy} or C _1-4 alkoxy;

R ^g and R ^j are each independently hydrogen, C _1-4 alkyl, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-C(=O)-, C _1-4 Alkyl-S(=O) ₂ -, C _3-6 cycloalkyl, C _6-10 aryl, heterocyclic group consisting of 5-6 atoms or heteroaryl group consisting of 5-6 atoms;

R ^m and R ⁿ are each independently hydrogen, deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, C 1-4 alkyl, halo C _1-4 alkyl or -C ( =O)NH ₂ ;

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

m and p are each independently 0, 1, 2 or 3.

、

、

、

、

或

。In some embodiments, Ring A is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazole base, indolyl, isoindolyl,

,

,

,

,

or

.

In some embodiments, R ³ is hydrogen, deuterium, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkyl-C (=O)-, HC(=O)-, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-S(=O) ₂ - or C _1-4 alkyl-C (=NH)-, wherein, the C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkyl-C (= O)-, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-S(=O) ₂ - and C _1-4 alkyl-C(=NH)- are each independently optional 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH ₂ to substituents.

In some embodiments, R ^a is hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclic of 5-6 atoms Cyclic group, phenyl group or heteroaryl group consisting of 5-6 atoms, wherein said C _1-4 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, C _3-6 cycloalkyl group , 5-6 atoms of heterocyclyl, phenyl and 5-6 atoms of heteroaryl are each independently optionally replaced by 1, 2, 3 or 4 selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH ₂ , -NO ₂ , -COOH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or a heterocycle composed of 5-6 atoms substituted by the substituents of the base.

In some embodiments, each R ^b is independently deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, -NO 2, -COOH, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-C(=O)-, C _1-4 alkyl-S(=O) _2- , C _3-6 cycloalkyl-C _1-4 alkyl, C _3-6 cycloalkyl, 5-6 atoms of heterocyclyl, phenyl, 5-6 atoms of heteroaryl, -NR ^e C(=O)C _1-4 alkyl, -NR ^e R ^f , -S(=O) ₂ -NR ^e R ^f , -C(=O)-NR ^e R ^f or -C _1-4 alkane base-NR ^e R ^f , wherein the C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl-C _1-4 alkyl, C _3-6 cycloalkyl, Phenyl, heterocyclyl of 5-6 atoms and heteroaryl of 5-6 atoms are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br, I, _{-OH, -CN, -NH 2, -NO} 2, -COOH, C 1-4 alkyl, substituted C _1-4 alkylamino or C _1-4 alkoxy substituents; wherein each of R ^e and R ^f has the meaning as described in the present invention.

In some embodiments, R ^e and R ^f are each independently hydrogen, C _1-4 alkyl, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-C(=O) -, C _1-4 alkyl-S(=O) ₂ -, C _3-6 cycloalkyl, C _6-10 aryl, 5-7 atoms heterocyclic group, 5-7 atoms Heteroaryl, heteroaryl consisting of 14-15 atoms, C _3-6 cycloalkyl-C _1-4 alkyl, C _6-10 aryl-C _1-4 alkyl, (5-7 atoms composed of heterocyclyl)-C _1-4 alkyl, (heteroaryl composed of 5-7 atoms)-C _1-4 alkyl or -C _1-4 alkyl-NR ^g R ^j ; or R ^e together with R ^f and their connected N atoms to form a heterocyclic group composed of 4-6 atoms; wherein, the heterocyclic groups composed of R ^e , R ^f and 4-6 atoms are each independently optionally replaced by 1 , 2, 3 or 4 R ^h ; wherein, each R ^h has the meaning as described in the present invention.

In some embodiments, R ² is 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, -CF 2 CH} 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CF 2 CH 2 CH 3, -CH 2 Cl, - CHCl ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, piperazinyl, piperidinyl, morpholinyl , thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl group, tetrahydrofuranyl group or pyrrolidinyl group; or R ² with R ^a and the atom thereof together form 1,3-dioxole, 1,3-dioxene, 2,3-dihydro-1,4,2-dioxazine or 1,5,3-dioxene Azacycloheptene, said 1,3-dioxole, 1,3-dioxene, 2,3-dihydro-1,4,2-dioxazine or 1 , 5,3- dioxo-azepine, optionally substituted independently selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, -CHF ₂ , -CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ or -CF ₂ CH ₃ substituents.

In some embodiments, R ³ is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy , n-propoxy, isopropoxy, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, HC(=O)-, methyl-C (=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC(=O)-, ethyl -OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) ₂ -, n-propyl-S(=O) ₂ -, isopropyl-S(=O) ₂ -, methyl-C(=NH)-, ethyl-C(=NH)-, n-propyl- C(=NH)- or isopropyl-C(=NH)-; wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertiary Butyl, methoxy, ethoxy, n-propoxy, isopropoxy, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, methyl Base-C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC(=O)- , ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-S(=O) ₂ -, ethyl-S(= O) ₂ -, n-propyl-S(=O) ₂ -, isopropyl-S(=O) ₂ -, methyl-C(=NH)-, ethyl-C(=NH)-, normal Propyl-C(=NH)- and isopropyl-C(=NH)- are each independently optionally replaced by 1, 2 or 3 selected from deuterium, F, Cl, Br, I, -OH, -CN or -NH ₂ substituent.

In some embodiments, R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ^{8 ,} and R ⁹ are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN , -NH ₂ , -NO ₂ , -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, iso-propoxy, -CH ₂ F, - CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CF ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , - _{CH 2 CH 2 CF 3, -CF} 2 CH 2 CH 3, -CH 2 Cl, -CHCl 2, methyl -C (= O) -, ethyl -C (= O) -, n-propyl -C ( =O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) ₂ -, n-propyl-S(=O) ₂ - or Isopropyl-S(=O) _2- .

In some embodiments, R ^a is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl , 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thio morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, Thiazolyl or oxazolyl; wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiophanyl Linyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazole and oxazolyl are independently optionally substituted with 1,2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, -NO 2, -COOH, methyl , ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, iso-propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piper Substituents of pyridyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl or pyrrolidinyl.

In some embodiments, each R ^b is independently deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, -NO 2, -COOH, oxo, methyl, ethyl, n-propyl base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, methyl-OC(=O)-, Ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, ethyl-C(=O) -, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) ₂ -, n-propyl- S(=O) ₂ -, isopropyl-S(=O) ₂ -, cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl n-propyl, cyclopropyl isopropyl, cyclobutyl methyl, Cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, -NR ^e C(=O) methyl, -NR ^e C(=O) ethyl, -NR ^e C(=O) n-propyl, -NR ^e C(=O) isopropyl, -NR ^e R ^f , - S(=O) ₂ -NR ^e R ^f , -C(=O)-NR ^e R ^f , -methyl-NR ^e R ^f , -ethyl-NR ^e R ^f , -n-propyl-NR ^e R ^f or -isopropyl-NR ^e R ^f ; wherein each R ^e and R ^f has the meaning as described in the present invention.

Among them, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropyl Oxy, cyclopropylmethyl, cyclopropylethyl, cyclopropyl-n-propyl, cyclopropylisopropyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl and oxazolyl are each independently optionally substituted by 1, 2, 3 or 4 selected from deuterium, F, Cl , Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, methyl, ethyl, n-propyl, isopropyl, methylamino, dimethylamino, methoxy, ethoxy , n-propoxy or isopropoxy substituent.

In some embodiments, R ^c and R ^{d are} each independently hydrogen, -OH, 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, -CF 2 CH 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CF 2 _{CH 2 CH 3, -CH 2 Cl} , -CHCl 2, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, methyl -C (= O) - , ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(= O) ₂ -, n-propyl-S(=O) ₂ - or isopropyl-S(=O) ₂ -.

；In some embodiments, R ^e and R ^{f are} each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl - OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, ethyl Base-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) _2- , n-propyl-S(=O) _2- , isopropyl-S(=O) _2- , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, piperazine base, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrole base, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, cyclopropylmethyl, cyclopropylethyl, cyclopropyln-propyl, cyclopropylisopropyl, cyclobutylmethyl, cyclopentylmethyl base, cyclohexylmethyl, benzyl, phenethyl, heterocyclyl-C _1-4 alkyl consisting of 5-7 atoms, pyridylmethyl, pyrimidinylmethyl, furylmethyl, thienyl group, a pyrrolyl group, a pyrazolyl group, imidazolyl group, thiazolyl group, oxazolyl group, - methyl -NR ^g R ^j, - ethyl -NR ^g R ^j, - n propyl-NR ^g R ^j , -isopropyl-NR ^g R ^j or

;

or R ^e and R ^{f taken} together with the N atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;

Wherein said R ^e, R ^f, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl each independently optionally substituted with 1,2, 3 or 4 R ^h is substituted; wherein, each R ^h has the meaning as described in the present invention.

In some embodiments, each R ^h is independently deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy , sec-butoxy or tert-butoxy;

R ^g and R ^j are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl-OC(=O)- , ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, ethyl-C(=O )-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) ₂ -, n-propyl -S(=O) ₂ -, isopropyl-S(=O) ₂ -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, piperazinyl, piperidinyl, morpholinyl , thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl or oxazolyl;

R ^m and R ⁿ are each independently hydrogen, deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, 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, -CF 2 CH 3, -CH 2 Cl, -CHCl 2 , or -C (= O) NH ₂ .

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

(II);

wherein each of X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ , A, R ^a , R ^b and n has meaning in the present invention.

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

(III);

wherein each of X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ , A, R ^a , R ^b and n has meaning in the present invention.

In some embodiments, the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumaric acid Salt, Malonate, Malate, 2-Hydroxypropionate, Pyruvate, Oxalate, Glycolate, Salicylate, Glucuronate, Galacturonate, Citrate , tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, mesylate, ethanesulfonate, trifluoromethanesulfonate salt or a combination thereof.

In another aspect, the present invention relates to a pharmaceutical composition comprising the compound represented by formula (I), (II) or (III) of the present invention or its stereoisomer, geometric isomer, tautomer, nitrogen oxide Compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs, and at least one of pharmaceutically acceptable excipients, carriers, adjuvants, adjuvants, vehicles or their combination;

The pharmaceutical composition further comprises other additional therapeutic agents, wherein the additional therapeutic agents are: sodium pyruvate, doxofylline, tetomilast, telukast, theophylline, formoterol, salmeterol, fluticasone propionate, rolipram, piramister, cilomilast, indacaterol, odaterol, midestane, qifluenza, salbutamol, carbamaze Luo, budesonide, beclomethasone dipropionate, flunisolide, roflunomide, ciclesonide, ipratropium bromide, oxytropium bromide, tiotropium bromide, glycopyrronium bromide, Destromium bromide, vilanterol, aclidinium bromide, Benralizumab, Tralokinumab, revatropate, cresabor, fluocinolone acetate, didometasone, mometasone, triamcinolone, betamethasone, aclomethasone, triamcinolone acetonide, desonide acetonide, hydrocortisone, clobetasol, halobetasol, mometasone furoate, diflurasone, meproclax, tacrolimus, pimecrolimus Limus, Tazarotene, Cyclosporine, Apremilast, E-6005, OPA-15406, LEO-29102, DRM02, Roflumilast, Ibudilast, Tofacitinib, JTE-052, Baricitinib, upadacitinib, WBI-1001, MRX-6, GSK2981278, durumumab, lekinizumab, nimolizumab, tralotinib, etanercept, Adalimumab, Infliximab, Utecalumab, Sekuginu, Omalizumab, CIM-331, Golimumab and Pegylated, Tocilizumab, Calcipotriol, Calcitriol, Aliretinoin, VTP-38543, ZPL-389, Aprepitant, Tridipitant, Faviprant, OC-459, SUN 13834, SB-011, VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02 or combinations thereof.

On the other hand, the present invention relates to the use of a compound represented by formula (I), (II) or (III) or a pharmaceutical composition thereof in the preparation of a medicament for preventing, treating or alleviating phosphodiester-type 4 Enzyme-related diseases.

In some embodiments, the present invention relates to the use of a compound represented by formula (I), (II) or (III) or a pharmaceutical composition thereof in the preparation of a medicament, wherein the disease related to phosphodiesterase type 4 is respiration Disease, allergy, inflammation, central nervous system disease or non-insulin dependent diabetes.

In some embodiments, the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, pulmonary fibrotic lesions, cystic fibrosis, acute Respiratory distress syndrome or inflammation of the respiratory tract; among them, bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis.

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

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

The biological test results show that the compounds provided by the present invention have good inhibitory activity to PDE4 and have good pharmacokinetic characteristics.

Any embodiment of any aspect of the invention may be combined with other embodiments so long as they do not appear to be inconsistent. Furthermore, in any embodiment of any aspect of the present invention, any technical feature may be applicable to that technical feature in other embodiments, as long as they do not contradict.

The foregoing has outlined but not limited aspects of the invention. These and other aspects are described in more detail below.

Definitions and General Terms

Certain embodiments of the present invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One of ordinary skill in the art would recognize that many methods and materials similar or equivalent to those described in the present invention could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts the present invention (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Invention shall prevail.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently 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 described in the present invention include, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, nitro, carboxyl, aryl, heteroaryl, alkoxy, alkyl, alkene alkynyl, alkynyl, heterocyclyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, oxo, haloalkyl, haloalkoxy, alkyl-C (=O)-, alkyl-OC(=O)-, alkyl-S(=O)-, alkyl-S(=O) ₂ -, alkylamino, NH ₂ -C(=O)- , NH ₂ -S(=O) ₂ -, and so on.

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

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

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

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

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH _3), ethyl _{(Et, -CH 2 CH 3)} , n-propyl _{(n -Pr, -CH 2 CH 2} CH 3 ), isopropyl _{(i -Pr, -CH (CH 3} ) 2), n-butyl _{(n -Bu, -CH 2 CH 2} CH 2 CH 3), isobutyl (i -Bu, -CH ₂ CH (CH ₃ ) ₂ ), sec-butyl ( s- Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl ( t -Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH _{2 CH 2 CH 2 CH 2 CH} 3), 2- pentyl _{(-CH (CH 3) CH 2} CH 2 CH 3), 3- pentyl _{(-CH (CH 2 CH 3)} 2), 2- methyl 2-butyl _{(-C (CH 3) 2 CH} 2 CH 3), 3- methyl-2-butyl _{(-CH (CH 3) CH (} CH 3) 2), 3- methyl-1- butyl _{(-CH 2 CH 2 CH (CH} 3) 2), 2- methyl-1-butyl _{(-CH 2 CH (CH 3)} CH 2 CH 3), n-hexyl (-CH ₂ CH ₂ CH _{2 CH 2 CH 2 CH 3),} 2- hexyl _{(-CH (CH 3) CH 2} CH 2 CH 2 CH 3), 3- hexyl _{(-CH (CH 2 CH 3)} (CH 2 CH 2 CH 3)), 2-methyl-2-pentyl _{(-C (CH 3) 2 CH} 2 CH 2 CH 3), 3- methyl-2-pentyl _{(-CH (CH 3) CH (} CH 3) CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, and the like.

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

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

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

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

The term "deuterium" refers to a single deuterium atom. For example, one deuterium atom replaces one hydrogen atom in methyl to form mono-deuteromethyl (-CDH ₂ ), and two deuterium atoms replace two hydrogen atoms in methyl to form bis-deuteromethyl (- CD ₂ H), and three deuterium atoms replace the three hydrogen atoms in the methyl group to form tri-deuteromethyl (-CD ₃ ).

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

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

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

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

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH _3), ethoxy _{(EtO, -OCH 2 CH 3)} , 1- propoxy (n -PrO, n- Propoxy, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy ( i- PrO, i -propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n- Butoxy, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propoxy ( i- BuO, i -butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy ( t- BuO, t -butoxy, -OC(CH _{3) 3),} 1-pentyl group (N- pentyloxy _{group, -OCH 2 CH 2 CH 2 CH} 2 CH 3), 2- pentyloxy group _{(-OCH (CH 3) CH 2} CH 2 CH 3), 3-pentyloxy (-OCH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butoxy (-OC(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butoxy group (-OCH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butoxy (-OCH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butoxy (-OCH ₂ CH(CH ₃ )CH ₂ CH ₃ ), etc.

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

The term "alkylamino" represents a -NH ₂ group substituted by one or two alkyl groups, wherein the alkyl group is as defined as the present invention. Unless otherwise specified, the alkylamino group contains 1-12 carbon atoms. In one embodiment, the alkylamino group contains 1-6 carbon atoms; in another embodiment, the alkylamino group contains 1-4 carbon atoms; in yet another embodiment, the alkylamino group contains 1 -3 carbon atoms. Examples of the alkylamino group include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, methylethylamino, and the like. The alkylamino group may be optionally substituted with one or more substituents described herein.

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

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

The terms "cycloalkyl-alkyl" or "cycloalkyl-alkylene" are used interchangeably and both refer to the substitution of an alkyl group by one or more cycloalkyl groups, wherein the alkyl group and the ring Alkyl groups have meanings as described herein, examples of which include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, Cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, etc.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, wherein the monocyclic, bicyclic or No aromatic rings are included in the tricyclic ring, and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise indicated, heterocyclyl groups may be carbon or nitrogen-based groups, and -CH ₂ - groups may be optionally substituted with -C (= O) - instead. Ring sulfur atoms can optionally be oxidized to S-oxides. The nitrogen atoms of the rings can optionally be oxidized to N -oxygen compounds. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, imidazolinyl , imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane, 1,3-dioxolyl, disulfide Amyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl , 1,1-dioxo-thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl . Heterocyclyl group -CH ₂ - group is -C (= O) - Examples of substituents include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl Keto and 3,5-dioxopiperidinyl. Examples of the oxidized sulfur atom in the heterocyclyl group include, but are not limited to, cyclobutanyl, 1,1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents described herein.

The terms "heterocyclyl-alkyl" or "heterocyclyl-alkylene" are used interchangeably, and both refer to a heterocyclyl-substituted alkyl group; meaning. Such examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydropyran-4-ylmethyl, oxetan-3-ylmethyl, Pyrrolidin-2-ylmethyl, morpholin-4-ylmethyl, etc.

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

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

The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-15 ring atoms, 5-12 ring atoms, or 5-10 ring atoms, or 5-7 ring atoms, of which at least one The ring systems are aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5-7 atoms with one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic", "aromatic heterocycle" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In some of these embodiments, a heteroaryl group of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S, N or B. In some of these embodiments, a heteroaryl group of 11-15 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S, N or B.

、

、

、

、

、

或

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

,

,

,

,

,

or

etc.

The terms "heteroaryl-alkyl" or "heteroaryl-alkylene" are used interchangeably and both refer to an alkyl group substituted with one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are group has the meaning set forth herein, such examples include, but are not limited to, pyridin-2ylmethyl, pyridin-3ylmethyl, pyridin-4ylmethyl, pyrimidin-2-ylmethyl, pyrazole-5 ylmethyl, pyrazol-4-ylmethyl, imidazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl and the like.

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

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

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

"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by conventional techniques in the art, and their activity can be characterized by experimental methods as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

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

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

"Hydrate" in the present invention refers to an association compound in which the solvent molecule is water. In some embodiments, one molecule of a compound of the present invention may be associated with one molecule of water, such as a monohydrate; in other embodiments, a molecule of a compound of the present invention may be associated with more than one molecule of water, such as a dihydrate In yet other embodiments, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compounds.

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

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

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

The term "therapeutically effective amount" or "therapeutically effective dose" as used herein refers to a biological or medical response in an individual (eg, reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a disorder, slowing or delaying a disease) development, or prevention of disease, etc.) of the compound of the present invention. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount effective to: (1) at least partially alleviate, inhibit, prevent and/or ameliorate when a compound of the present invention is administered to an individual (i) associated with PDE4, or (ii) associated with PDE4 activity, or (iii) a disorder or disease characterized by abnormal activity of PDE4; or (2) decreased or inhibited the activity of PDE4; or (3) decreased or inhibited PDE4 expression. In another embodiment, the term "therapeutically effective amount" refers to at least partially reducing or inhibiting PDE4 activity; or at least partially reducing or inhibiting PDE4 activity when administered to cells, or organs, or non-cellular biological substances, or mediators The amount of effective compound of the invention expressed by PDE4.

The terms "administering" and "administering" a compound as used herein are to be understood as providing a compound of the present invention or a prodrug of a compound of the present invention to an individual in need thereof. It will be appreciated that one of ordinary skill in the art can treat patients currently suffering from the disorder or prophylactically treat patients suffering from the disorder by administering an effective amount of a compound of the present invention.

The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of this term in relation to a pharmaceutical composition includes a product comprising the active ingredient (single or multiple) and inert ingredient (single or multiple) constituting the carrier, as well as being mixed, compounded or aggregated from any two or more ingredients, or any product that results directly or indirectly from the decomposition of one or more components, or from other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

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

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

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

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

Description of Compounds of the Invention

The present invention relates to novel pyrrolidine compounds and methods of treating atopic dermatitis or chronic obstructive pulmonary disease. As a PDE4 inhibitor, the compound of the present invention or the pharmaceutical composition comprising the compound has a good therapeutic effect on atopic dermatitis or chronic obstructive pulmonary disease.

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

(I);

wherein each of X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ , A, R ^b and n has the stated meaning.

In some embodiments, X is CH or N.

In some embodiments, Y is _{- (CH 2) m -C (} = O) -NH- (CR m R n) p - or _{- (CH 2) m -C (} = O) -O- (CR m R ⁿ ) _p -; wherein R ^m , R ⁿ , m and p have the meanings described in the present invention.

In some embodiments, Ring A is a C _6-10 aryl group or a heteroaryl group consisting of 5-10 atoms.

In some embodiments, R ¹ is hydrogen, deuterium, -OR ^a or -NR ^c R ^d ; wherein ^Ra , R ^c and R ^d have the meanings described herein.

In some embodiments, R ² is C _1-4 alkyl, haloC _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl, 5- Heterocyclyl consisting of 7 atoms or (heterocyclyl consisting of 5-7 atoms)-C _1-4 alkyl; or

R ² and R ^a and the connected atoms together form a heterocyclic group composed of 5-7 atoms, and the heterocyclic group composed of 5-7 atoms is optionally selected from deuterium, F, Cl, Br, Substituents of I, -OH, -CN, -NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or halogenated C _{1-4 alkyl.}

In some embodiments, R ³ is hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, HC(=O)-, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-S(=O) ₂ - or C _1-6 alkyl-C (=NH)-, wherein said C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl-C(=O )-, C _1-6 alkyl-S(=O) ₂ - and C _1-6 alkyl-C(=NH)- each independently optionally selected from 1, 2 or 3 deuterium, F, Cl, Substituents of Br, I, -OH, -CN or -NH ₂ are substituted.

In some embodiments, R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ^{8 ,} and R ⁹ are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN , -NH ₂ , -NO ₂ , -COOH, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, C _1-4 alkyl -C(=O)- or C _1-4 alkyl-S(=O) ₂ -.

In some embodiments, R ^a is hydrogen, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, heterocyclic consisting of 5-10 atoms Cyclic group, C _6-10 aryl group or heteroaryl group consisting of 5-10 atoms, wherein said C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-8 Cycloalkyl, heterocyclyl of 5-10 atoms, C _6-10 aryl, and heteroaryl of 5-10 atoms are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or 5- Substituted by the substituent of a heterocyclic group consisting of 10 atoms.

In some embodiments, each R ^b is independently deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, -NO 2, -COOH, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O) _2- , C _3-8 cycloalkyl-C _1-6 alkyl, C _3-8 cycloalkyl, heterocyclic group consisting of 5-10 atoms, C _6-10 aryl group, heteroaryl consisting of 5-10 atoms base, -NR ^e C(=O)C _1-6 alkyl, -NR ^e R ^f , -S(=O) ₂ -NR ^e R ^f , -C(=O)-NR ^e R ^f or -C _1-6 alkyl-NR ^e R ^f , wherein said C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl-C _1-6 alkyl, C _3-8 ring Alkyl, heterocyclyl of 5-10 atoms, C _6-10 aryl and heteroaryl of 5-10 atoms are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F , Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkylamino or C _1-6 alkoxy substituents ; wherein, R ^e and R ^f are each have the meaning of the present invention.

In some embodiments, R ^c and R ^d are each independently hydrogen, -OH, C _1-4 alkyl, haloC _1-4 alkyl, C _3-6 cycloalkyl-C _1-4 alkyl , C _3-6 cycloalkyl, heterocyclyl composed of 5-7 atoms, (heterocyclyl composed of 5-7 atoms)-C _1-4 alkyl, C _1-4 alkyl-C (= O)- or C _1-4 alkyl-S(=O) ₂ -.

In some embodiments, R ^e and R ^f are each independently hydrogen, C _1-6 alkyl, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O) -, C _1-6 alkyl-S(=O) ₂ -, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 atoms heterocyclic group, 5-10 atoms Heteroaryl, heteroaryl consisting of 11-15 atoms, C _3-8 cycloalkyl-C _1-6 alkyl, C _6-10 aryl-C _1-6 alkyl, (5-10 atoms composed of heterocyclyl)-C _1-6 alkyl, (heteroaryl composed of 5-10 atoms)-C _1-6 alkyl or -C _1-6 alkyl-NR ^g R ^j ; or R ^e together with R ^f and their connected N atoms to form a heterocyclic group composed of 4-7 atoms; wherein, the heterocyclic groups composed of R ^e , R ^f and 4-7 atoms are each independently optionally replaced by 1 , 2, 3 or 4 R ^h ;

Wherein, each of R ^g , R ^j and R ^h has the meaning described in the present invention.

In some embodiments, each R ^h is independently deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, C 1-4 alkyl, C _{1-4 haloalkyl} -alkyl, C _{1 -4 haloalkoxy} or C _1-4 alkoxy.

R ^g and R ^j are each independently hydrogen, C _1-4 alkyl, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-C(=O)-, C _1-4 Alkyl-S(=O) ₂ -, C _3-6 cycloalkyl, C _6-10 aryl, heterocyclic group consisting of 5-6 atoms or heteroaryl group consisting of 5-6 atoms.

In some embodiments, R ^m and R ⁿ are each independently hydrogen, deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, C 1-4 alkyl, halo C _1-4 alkyl or -C (= O) NH _2.

In some embodiments, each n is independently 0, 1, 2, 3, or 4.

In some embodiments, m and p are each independently 0, 1, 2, or 3.

、

、

、

或

。In other embodiments, Ring A is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxa azolyl, indolyl, isoindolyl,

,

,

,

or

.

In other embodiments, R ³ is hydrogen, deuterium, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkyl- C(=O)-, C _1-4 alkyl-OC(=O)-, HC(=O)-, C _1-4 alkyl-S(=O) ₂ - or C _1-4 alkyl- C(=NH)-, wherein said C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkyl-C(= O)-, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-S(=O) ₂ - and C _1-4 alkyl-C(=NH)- are each independently optional 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH ₂ to substituents.

In other embodiments, R ^a is hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, consisting of 5-6 atoms Heterocyclic group, phenyl group or heteroaryl group consisting of 5-6 atoms, wherein the C _1-4 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, C _3-6 cycloalkane group base, 5-6 atoms heterocyclyl, phenyl and 5-6 atoms heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or a hetero group consisting of 5-6 atoms substituted by the substituent of the cyclic group.

In other embodiments, each R ^b is independently deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, -NO 2, -COOH, oxo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-C(=O)-, C _1-4 alkyl-S(=O) _2- , C _3-6 cycloalkyl-C _1-4 alkyl, C _3-6 cycloalkyl, heterocyclic group consisting of 5-6 atoms, phenyl, heteroaryl group consisting of 5-6 atoms, - NR ^e C(=O)C _1-4 alkyl, -NR ^e R ^f , -S(=O) ₂ -NR ^e R ^f , -C(=O)-NR ^e R ^f or -C _1-4 Alkyl-NR ^e R ^f , wherein said C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl-C _1-4 alkyl, C _3-6 cycloalkyl, Phenyl, heterocyclyl of 5-6 atoms and heteroaryl of 5-6 atoms are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br, I, _{-OH, -CN, -NH 2, -NO} 2, -COOH, C 1-4 alkyl, substituted C _1-4 alkylamino or C _1-4 alkoxy substituents; wherein each of R ^e and R ^f has the meaning described in the present invention.

In other embodiments, R ^e and R ^f are each independently hydrogen, C _1-4 alkyl, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-C(=O )-, C _1-4 alkyl-S(=O) ₂ -, C _3-6 cycloalkyl, C _6-10 aryl, heterocyclic group composed of 5-7 atoms, composed of 5-7 atoms Heteroaryl, heteroaryl consisting of 14-15 atoms, C _3-6 cycloalkyl-C _1-4 alkyl, C _6-10 aryl-C _1-4 alkyl, (5-7 atomic heterocyclyl)-C _1-4 alkyl, (5-7 atom heteroaryl)-C _1-4 alkyl or -C _1-4 alkyl-NR ^g R ^j ; or R ^e and R ^f together with the N atom to which they are attached form a heterocyclic group consisting of 4-6 atoms; wherein said R ^e , R ^f and the heterocyclic group consisting of 4-6 atoms are each independently optionally replaced by 1 , 2, 3 or 4 R ^h ; wherein, each R ^h , R ^g and R ^j has the meaning described in the present invention.

In still other embodiments, R ² is 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, -CF 2 CH} 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CF 2 CH 2 CH 3, -CH 2 Cl, -CHCl ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, piperazinyl, piperidinyl, morpholine thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl or pyrrolidinylmethyl; or

）、1,3-二氧雜環己烯、2,3-二氫-1,4,2-二噁嗪烯或1,5,3-二氧氮雜環庚烯，所述的1,3-二氧雜環戊烯、1,3-二氧雜環己烯、2,3-二氫-1,4,2-二噁嗪烯或1,5,3-二氧氮雜環庚烯獨立任選地被選自氘、F、Cl、Br、I、-OH、-CN、-NH₂ 、甲基、乙基、正丙基、異丙基、正丁基、異丁基、仲丁基、叔丁基、甲氧基、乙氧基、正丙氧基、異丙氧基、-CHF₂ 、-CF₃ 、-CH₂ CHF₂ 、-CH₂ CF₃ 或-CF₂ CH₃ 的取代基所取代。And R ^a and R ² thereof atom together form 1,3-dioxole (

), 1,3-dioxene, 2,3-dihydro-1,4,2-dioxazine or 1,5,3-dioxane, said 1, 3-dioxole, 1,3-dioxene, 2,3-dihydro-1,4,2-dioxazine or 1,5,3-dioxazepan alkenyl optionally substituted with independently selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CHF ₂ , -CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ or -CF ₂ CH ₃ of substituents.

In still other embodiments, R ³ is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy group, n-propoxy, isopropoxy, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, HC(=O)-, methyl- C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC(=O)-, ethyl Base-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) _2- , n-propyl-S(=O) _2- , isopropyl-S(=O) _2- , methyl-C(=NH)-, ethyl-C(=NH)-, n-propyl -C(=NH)- or isopropyl-C(=NH)-;

Among them, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropyl Oxy, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, methyl-C(=O)-, ethyl-C(=O)- , n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(= O)-, isopropyl-OC(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) ₂ -, n-propyl-S(=O) ₂ -, isopropyl Propyl-S(=O) ₂ -, methyl-C(=NH)-, ethyl-C(=NH)-, n-propyl-C(=NH)- and isopropyl-C(=NH)- ) - are each independently optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH ₂ to a substituent group.

In yet other embodiments, R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ^{8 ,} and R ⁹ are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, - CN, -NH ₂ , -NO ₂ , -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, iso-propoxy, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CF ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , _{-CH 2 CH 2 CF 3, -CF} 2 CH 2 CH 3, -CH 2 Cl, -CHCl 2, methyl -C (= O) -, ethyl -C (= O) -, n-propyl -C (=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) ₂ -, n-propyl-S(=O) ₂ - or isopropyl-S(=O) ₂ -.

In still other embodiments, R ^a is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl base, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, sulfur morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl , thiazolyl or oxazolyl;

Among them, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, ethynyl , 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyran , tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, and oxazolyl are each independently optionally substituted with 1,2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, -NO 2, -COOH, methyl, ethyl, n-propyl , isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, Substituents of thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl or pyrrolidinyl.

In still other embodiments, each R ^b is independently deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, -NO 2, -COOH, oxo, methyl, ethyl, n Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, methyl-OC(=O)- , ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, ethyl-C(=O )-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) ₂ -, n-propyl -S(=O) ₂ -, isopropyl-S(=O) ₂ -, cyclopropylmethyl, cyclopropylethyl, cyclopropyl-n-propyl, cyclopropylisopropyl, cyclobutylmethyl , cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl , tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, -NR ^e C(=O) methyl, -NR ^e C(=O) ethyl, -NR ^e C(=O) n-propyl, -NR ^e C(=O) isopropyl, -NR ^e R ^f , -S(=O) ₂ -NR ^e R ^f , -C(=O)-NR ^e R ^f , -methyl-NR ^e R ^f , -ethyl-NR ^e R ^f , -n-propyl-NR ^e R ^f or -isopropyl-NR ^e R ^f ;

Among them, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropyl Oxy, cyclopropylmethyl, cyclopropylethyl, cyclopropyl-n-propyl, cyclopropylisopropyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl and oxazolyl are each independently optionally substituted by 1, 2, 3 or 4 selected from deuterium, F, Cl , Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, methyl, ethyl, n-propyl, isopropyl, methylamino, dimethylamino, methoxy, ethoxy , n-propoxy or isopropoxy substituent;

Wherein, R ^e and R ^f are each have the meaning of the present invention.

In still other embodiments, R ^c and R ^{d are} each independently hydrogen, -OH, 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, -CF 2 CH 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF 3, -CF _{2 CH 2 CH 3, -CH 2} Cl, -CHCl 2, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, methyl -C (= O) -, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S( =O) ₂ -, n-propyl-S(=O) ₂ - or isopropyl-S(=O) ₂ -.

；In still other embodiments, R ^e and R ^{f are} each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl -OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, Ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O ) ₂ -, n-propyl-S(=O) ₂ -, isopropyl-S(=O) ₂ -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, piper Azinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, Pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, cyclopropylmethyl, cyclopropylethyl, cyclopropyl-n-propyl, cyclopropylisopropyl, cyclobutylmethyl, cyclopentyl Methyl, cyclohexylmethyl, benzyl, phenethyl, heterocyclyl-C _1-4 alkyl of 5-7 atoms, pyridylmethyl, pyrimidinylmethyl, furylmethyl, thiophene group, a pyrrolyl group, a pyrazolyl group, imidazolyl group, thiazolyl group, oxazolyl group, - methyl -NR ^g R ^j, - ethyl -NR ^g R ^j, - n-propyl-NR ^g R ^j , -isopropyl-NR ^g R ^j or

;

or R ^e and R ^{f taken} together with the N atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;

Wherein said R ^e, R ^f, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl each independently optionally substituted with 1,2, 3 or Replaced by 4 R ^h;

Wherein, each of R ^h , R ^g and R ^j has the meaning described in the present invention.

In still other embodiments, each R ^h is independently deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy group, sec-butoxy or tert-butoxy.

In yet other embodiments, R ^g and R ^j are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methyl -OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, Ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O ) ₂ -, n-propyl-S(=O) ₂ -, isopropyl-S(=O) ₂ -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, Pyrazolyl, imidazolyl, thiazolyl or oxazolyl.

In still other embodiments, R ^m and R ⁿ are each independently hydrogen, deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, methyl, ethyl, n-propyl, isopropyl, _{group, -CH 2 F, -CHF 2,} -CF 3, -CH 2 CH 2 F, -CH 2 CHF 2, -CH 2 CF 3, -CF 2 CH 3, -CH 2 Cl, -CHCl 2 , or - C (= O) NH _2.

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

(II);

wherein each of X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ , A, R ^a , R ^b and n has meaning in the present invention.

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

(III);

wherein each of X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ , A, R ^a , R ^b and n has meaning in the present invention.

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

(IV);

wherein each of X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ , A, R ^a , R ^b and n has meaning in the present invention.

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

(V);

wherein each of X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ , A, R ^a , R ^b and n has meaning in the present invention.

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

(VI);

wherein each of X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ , A, R ^a , R ^b and n has meaning in the present invention.

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

(VII);

wherein each of X, Y, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ , R ⁹ , A, R ^a , R ^b and n has meaning in the present invention.

(1)、

(2)、

(3)、

(4)、

(5)、

(6)、

(7)、

(8)、

(9)、

(10)、

(11)、

(12)、

(13)、

(14)、

(15)、

(16)、

(17)、

(18)、

(19)、

(20)、

(21)、

(22)、

(23)、

(24)、

(25)、

(26)、

(27)、

(28)、

(29)、

(30)、

(31)、

(32)、

(33)、

(34)、

(35)、

(36)、

(37)、

(38)、

(39)、

(40)、

(41)、

(42)、

(43)、

(44)、

(45)、

(46)、

(47)、

(48)、

(49)、

(50)、

(51)、

(52)、

(53)、

(54)、

(55)、

(56)、

(57)、

(58)、

(59)、

(60)、

(61)、

(62)、

(63)、

(64)、

(65)、

(66)、

(67)、

(68)、

(69)、

(70)、

(71)、

(72)、

(73)、

(74)、

(75)、

(76)、

(77)、

(78)、

(79)、

(80)、

(81)、

(82)、

(83)、

(84)、

(85)、

(86)、

(87)、

(88)、

(89)、

(90)、

(91)、

(92)、

(93)、

(94)、

(95)、

(96)、

(97)、

(98)、

(99)、

(100)、

(101)、

(102)、

(103)、

(104)、

(105)、

(106)、

(107)、

(108)、

(109)、

(110)、

(111)、

(112)、

(113)、

(114)、

(115)、

(116)、

(117)、

(118)、

(119)、

(120)、

(121)、

(122)、

(123)、

(124)、

(125)、

(126)、

(127)、

(128)、

(129)、

(130)、

(131)、

(132)、

(133)、

(134)、

(135)、

(136)、

(137)、

(138)、

(139)、

(140)、

(141)、

(142)、

(143)、

(144)、

(145)、

(146)、

(147)、

(148)、

(149)、

(150)、

(151)、

(152)、

(153)、

(154)、

(155)、

(156)、

(157)、

(158)、

(159)、

(160)、

(161)、

(162)、

(163)、

(164)、

(165)、

(166)、

(167)、

(168)、

(169)、

(170)、

(171)、

(172)、

(173)、

(174)、

(175)、

(176)、

(177)、

(178)、

(179)、

(180)、

(181)、

(182)、

(183)、

(184)、

(185)、

(186)、

(187)、

(188)、

(189)、

(190)、

(191)、

(192)、

(193)、

(194)、

(195)、

(196)、

(197)、

(198)、

(199)、

(200)、

(201)、

(202)、

(203)、

(204)、

(205)、

(206)、

(207)、

(208)、

(209)、

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(233)、

(234)、

(235)、

(236)、

(237)、

(238)、

(239)、

(240)、

(241) 或

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

(1),

(2),

(3),

(4),

(5),

(6),

(7),

(8),

(9),

(10),

(11),

(12),

(13),

(14),

(15),

(16),

(17),

(18),

(19),

(20),

(twenty one),

(twenty two),

(twenty three),

(twenty four),

(25),

(26),

(27),

(28),

(29),

(30),

(31),

(32),

(33),

(34),

(35),

(36),

(37),

(38),

(39),

(40),

(41),

(42),

(43),

(44),

(45),

(46),

(47),

(48),

(49),

(50),

(51),

(52),

(53),

(54),

(55),

(56),

(57),

(58),

(59),

(60),

(61),

(62),

(63),

(64),

(65),

(66),

(67),

(68),

(69),

(70),

(71),

(72),

(73),

(74),

(75),

(76),

(77),

(78),

(79),

(80),

(81),

(82),

(83),

(84),

(85),

(86),

(87),

(88),

(89),

(90),

(91),

(92),

(93),

(94),

(95),

(96),

(97),

(98),

(99),

(100),

(101),

(102),

(103),

(104),

(105),

(106),

(107),

(108),

(109),

(110),

(111),

(112),

(113),

(114),

(115),

(116),

(117),

(118),

(119),

(120),

(121),

(122),

(123),

(124),

(125),

(126),

(127),

(128),

(129),

(130),

(131),

(132),

(133),

(134),

(135),

(136),

(137),

(138),

(139),

(140),

(141),

(142),

(143),

(144),

(145),

(146),

(147),

(148),

(149),

(150),

(151),

(152),

(153),

(154),

(155),

(156),

(157),

(158),

(159),

(160),

(161),

(162),

(163),

(164),

(165),

(166),

(167),

(168),

(169),

(170),

(171),

(172),

(173),

(174),

(175),

(176),

(177),

(178),

(179),

(180),

(181),

(182),

(183),

(184),

(185),

(186),

(187),

(188),

(189),

(190),

(191),

(192),

(193),

(194),

(195),

(196),

(197),

(198),

(199),

(200),

(201),

(202),

(203),

(204),

(205),

(206),

(207),

(208),

(209),

(210),

(211),

(212),

(213),

(214),

(215),

(216),

(217),

(218),

(219),

(220),

(221),

(222),

(223),

(224),

(225),

(226),

(227),

(228),

(229),

(230),

(231),

(232),

(233),

(234),

(235),

(236),

(237),

(238),

(239),

(240),

(241) or

(242).

In some embodiments, the compound represented by formula (I) of the present invention, its pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate , succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, pyruvate, oxalate, glycolate, salicylate, glucuronic acid Salt, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate salts, ethanesulfonates, triflates, or combinations thereof.

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

In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, adjuvant, vehicle or any combination thereof.

In other embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, telukast , theophylline, formoterol, salmeterol, fluticasone propionate, rolipram, piramister, cilomilast, indacaterol, odaterol, midestane, qifluu , salbutamol, camoxirol, budesonide, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, roflunomide, ciclesonide, ipratropium bromide Ammonium, oxtropium, tiotropium, glycopyrronium, umeclidinium, vilanterol, aclidinium, benralizumab, Tralokinumab, revatropate, cresabor, fluocinolone acetate , Desoxymetasone, Mometasone, Triamcinolone, Betamethasone, Aclometasone, Desonide, Hydrocortisone, Clobetasol (clobatsol), Halobetasol, Diflurasone, Meptocline, Tacrolimus, Pimecrolimus, Tazarotene, Cyclosporine, Apremilast, E-6005, OPA-15406, LEO-29102, DRM02, Roflumilast, Ibuprofen Sturt, tofacitinib, JTE-052, baricitinib, upatinib, WBI-1001, MRX-6, GSK2981278, durumumab, lekinizumab, nimolizumab, Traloginumab, etanercept, adalimumab, infliximab, ustekinumab, secukinumab, omalizumab, CIM-331, golimumab, and pegylated acepirin, tocilizumab, calcipotriol, calcitriol, alicitretin, VTP-38543, ZPL-389, aprepitant, tripitant, faviprant, OC-459, SUN 13834, SB-011, VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02 or any combination thereof.

On the other hand, the present invention relates to the use of the compounds of formula (I), (II), (III), (IV), (V) or (VI) disclosed in the present invention or their pharmaceutical compositions in the preparation of medicines, Wherein, the medicine is used for preventing, treating or alleviating diseases related to phosphodiesterase type 4 (PDE4).

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

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

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

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

In another aspect, the present invention relates to intermediates for the preparation of compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII).

Compounds of the present disclosure may contain asymmetric or chiral centers and, therefore, may exist in different stereoisomeric forms. The present invention is intended to make all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers Compounds, as well as mixtures thereof such as racemic mixtures, form part of the present invention.

In a structure disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the present invention as compounds disclosed herein . When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, then the stereoisomers of that structure are identified and defined.

Compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) may exist in different tautomeric forms, and all these tautomers, All are included in the scope of the present invention.

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

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

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

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

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

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

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

In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New Various carriers for formulating pharmaceutically acceptable compositions, and general techniques for their preparation, are disclosed in York, the contents of each of which are incorporated herein by reference. Except for any conventional carrier that is incompatible with the compounds of the present invention, such as by producing any undesired biological effect, or interacting in a deleterious manner with any other ingredient of the pharmaceutically acceptable composition, concerns for its use are within the scope of this scope of invention.

Suitable pharmaceutically acceptable carriers depend on the pharmaceutical form and are known to those of ordinary skill in the art.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Preferably, the route of administration will vary with clinical characteristics, the dosage will depend on the condition of the patient being treated, and the physician will determine the appropriate dosage on an individual patient basis. The therapeutically effective amount per unit dose depends on body weight, physiology and the chosen vaccination regimen. Compound per unit dose refers to the weight of the compound per administration, excluding the weight of the carrier (which is contained in the drug).

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

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

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

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

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

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

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

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

(1) β2-agonists, such as salbutamol, formoterol, salmeterol and camoxirol;

(2) Corticosteroids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, flunisolide, mometasone furoate, roflunomide, ciclesonide, fluocinolone acetonide, didanoate Methasone, Mometasone, Triamcinolone, Betamethasone, Aclometasone, Desonide, Hydrocortisone, Meproclair;

(3) Anticholinergic or antimuscarinic drugs, such as ipratropium bromide, oxytropium bromide, tiotropium bromide, glycopyrronium bromide, revatropate;

(4) Topical calcineurin inhibitors, such as tacrolimus, pimecrolimus, cyclosporine;

(5) Topical preparations of PDE4 inhibitors, such as Apremilast, Ibudilast, E-6005, OPA-15406, LEO-29102, DRM02, Roflumilast, Cresaborone;

(6) Topical preparations of JAK kinase inhibitors, such as tofacitinib, JTE-052, baricitinib, upatinib;

(7) Topical non-steroidal anti-inflammatory drugs, such as WBI-1001, MRX-6;

(8) Topical ROR agents, such as GSK2981278;

(9) Injectable anti-IL4, IL-31, IL-22, IL-33, IL-12, IL-23, IL-17, IgE, IL-4 therapeutic drugs, such as Dupilumab, Akinizumab, Nemolizumab, Tralokinumab, Etanercept, Adalimumab, Infliximab, Utecalumab, Secukinumab , Omazumilab, CIM-331;

(10) Vitamin D analogs, such as calcipotriol, calcitriol;

(11) Oral retinoic acid derivatives, such as alivet A acid;

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

(13) Oral H4 receptor antagonists, such as ZPL-389;

(14) Oral NK1 receptor antagonists, such as aprepitant and tripipitant;

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

(16) Oral chymotrypsin inhibitors such as SUN 13834.

Preferably, the compound of formula (I) or formula (II) is administered alone or in combination with other active ingredients 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.

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

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

Use of the Compounds and Pharmaceutical Compositions of the Invention

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

General synthetic steps

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

One of ordinary skill in the art will recognize that the chemical reactions described in this invention can be used to suitably prepare many other compounds of this invention, and that other methods for preparing compounds of this invention are considered within the scope of this invention. within the range. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by one of ordinary skill in the art by modifying methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, Or make some routine modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.

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

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

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

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

Low-resolution mass spectrometry (MS) data were determined under the following conditions: 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: ratio of 5% -95% (containing 0.1% formic acid in CH ₃ CN) in (H containing 0.1% formic acid ₂ O) in)), with UV detection at 210/254 nm, electrospray ionization mode (ESI).

The purity of the compounds was characterized by: Agilent 1260 Preparative High Performance Liquid Chromatography (Pre-HPLC) or Calesep Pump 250 Preparative High Performance Liquid Chromatography (Pre-HPLC) (column type: NOVASEP, 50/80 mm, DAC), Detection with UV at 210 nm/254 nm.

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

Analytical method:

1. Use an AS-H column (manufacturer: Daicel, size: 4.6 × 250 mm, 5 μm), mobile phase conditions: column temperature 30 °C, flow rate 1 mL/min, 30% ethanol (0.1% trifluoroacetic acid), 70% n-hexane;

2. Use OD-H column (manufacturer: Daicel, size: 4.6 × 250 mm, 5 μm) mobile phase conditions: column temperature 30 °C, flow rate 1 mL/min, 30% ethanol, 70% n-hexane;

3. Use an IC column (manufacturer: Daicel, size: 4.6 × 250 mm, 5 μm) mobile phase conditions: column temperature 30°C, flow rate 0.8 mL/min, 50% ethanol, 50% n-hexane.

The following abbreviations are used throughout this disclosure: CD ₃ OD Deuterated methanol DMSO- d ₆ deuterated dimethyl sulfoxide CDCl ₃ deuterated chloroform HCl hydrochloric acid Pd/C Palladium on carbon mol Moore h Hour min minute L Rise mL, ml ml M, mol/L moles/liter HPLC high performance liquid chromatography GC Gas chromatography MHz megahertz BnOH benzyl alcohol Tf ₂ O Trifluoromethanesulfonic anhydride DIPEA N , N -diisopropylethylamine TEA triethylamine Boc tert-Butoxycarbonyl Bu tert-butyl DMF N , N -dimethylformamide DCM Dichloromethane MeOH methanol

Synthesis of intermediates:

Important intermediates M-4 can be prepared by synthetic methods of intermediates wherein, unless otherwise stated, R ² and R ^a have the meanings as described in the present invention. The starting material M-1 and the material BnOH undergo rearrangement reaction under the condition of weak base and diphenylphosphoric azide to form an amino protecting group to obtain intermediate M-2, and intermediate M-2 undergoes catalytic hydrogenation reduction to obtain intermediate M -3, the intermediate M-3 undergoes a diazotization reaction, and then undergoes a substitution reaction with KI to obtain the intermediate M-4.

Target product synthesis method:

Synthesis method one:

The target compound S-8 can be prepared by synthetic method 1, wherein, X represents a halogen atom, R ^x is -NH ₂ or -OH, R ^xo is -NH- or -O-, unless otherwise specified, A ring, R ² , R ^a , R ^b , R ^m , R ⁿ , p and n have the meanings as described in the present invention. Compound S-1 is subjected to enolation reaction under basic conditions (such as DIPEA or TEA, etc.) and then undergoes substitution reaction to obtain compound S-2. Compound S-2 and compound S'-2 undergo boronylation under basic conditions Reaction to obtain compound S-3, compound S-3 and intermediate M-4 undergo Suzuki coupling reaction under coupling reagent conditions to obtain compound S-4, compound S-4 is subjected to catalytic hydrogenation to obtain compound S-5, compound S- 5 Under acidic conditions, the Boc protecting group was removed, and then compound S-6 was obtained by acylation reaction, and compound S-6 was obtained by ester hydrolysis reaction under basic conditions to obtain compound S-7. Compound S-7 and compound S'- 7 The target compound S-8 is obtained by condensation reaction under the action of a suitable condensing agent.

Synthesis method two:

The target compound S-11 can be prepared by synthetic method 2, wherein, R ^x is -NH ₂ or -OH, R ^xo is -NH- or -O-, unless otherwise specified, A ring, R ² , R ^a , R ^{e, R f, R m,} R n and p have the meanings as described in the present invention. Compound S-7 and compound S''-7 undergo condensation reaction under the action of a suitable condensing agent to obtain compound S-9, compound S-9 undergoes ester hydrolysis under basic conditions to obtain compound S-10, compound S-10 The target compound S-11 is obtained by condensation reaction with compound S'-10 under the action of a suitable condensing agent.

Synthesis of Intermediates

Intermediate 1: 2-(Cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene

Step 1: Synthesis of compound (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)carbamate benzyl

3-(Cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (5.0 g, 19.4 mmol) was dissolved in toluene (25 mL) and diphenylphosphoryl azide (5.0 mL, 23.0 mL) was added. mmol), triethylamine (4.3 mL, 31.0 mmol), react at room temperature for 1 h, add benzyl alcohol (3.0 mL, 29.0 mmol), transfer to 90 °C and heat for 3 h. Concentrated under reduced pressure to remove the solvent, the residue was added with water (100 ml), extracted 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: petroleum ether/ethyl acetate (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] ⁺ .

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

Benzyl (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)carbamate (145 mg, 0.45 mmol) was dissolved in anhydrous methanol (6 mL) and palladium was added Carbon (50 mg) was removed, and hydrogen was passed through to react at room temperature for 2 h. The catalyst was removed by suction filtration with diatomaceous earth, and the filtrate was concentrated to obtain 102 mg of a light red liquid with a yield of 98%.

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

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

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

Compound 3-(cyclopropylmethoxy)-4-(difluoromethoxy)aniline hydrochloride (17 g, 64.0 mmol) was dissolved in 1,4-dioxane (85 mL) and water (30 mL), add concentrated hydrochloric acid (17 mL) below 0 °C, cool down to -15 °C, add a solution of sodium nitrite (5.3 g, 77.0 mmol) and water (15 mL) dropwise, and control the temperature at -15 °C. Between ℃ and -5℃, continue the reaction for 40 min at 0℃, add a solution of potassium iodide (13.8 g, 83.1 mmol) and water (15 mL), control the temperature between -15℃ and -5℃, and complete the dropwise addition. After that, the reaction was continued at 0 °C for 2 h, water (200 mL) was added to stop the reaction, extracted with ethyl acetate (200 mL × 2), the organic phase was washed once with saturated sodium sulfite, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pale Brown liquid 21 g, yield 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 2: Intermediate 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene

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

Compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (4.9 g, 14.0 mmol) was dissolved in acetonitrile (8 mL), water (10 mL) and Concentrated hydrochloric acid (10 mL), react at 80 °C for 4 h, add sodium hydroxide solution to adjust pH=5, extract with ethyl acetate (5 mL × 3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and concentrate the solution for silica gel Column chromatography separation (eluent: petroleum ether/ethyl acetate (v/v) = 5/1) gave 1.8 g of pale yellow liquid with a yield of 44%.

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

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

Step 2: Synthesis of compound 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 mixed in N , N -dimethylformamide (30 mL) Homogeneous, added benzyl bromide (2.5 mL, 21.0 mmol), reacted at 100 °C for 16 h, filtered to remove the solid, concentrated the filtrate, added water (50 mL), extracted with ethyl acetate (25 mL × 3), the organic phase was combined with anhydrous After drying over sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1) to obtain 4.8 g of pale yellow liquid with a yield of 96%.

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

Intermediate 3: Intermediate 6-(aminomethyl) -N,N -lutidine pyridinamide dihydrochloride

Step 1: Synthesis of compound 6-(((tert-butoxycarbonyl)amino)methyl)picolinate ethyl ester

Ethyl 6-(aminomethyl)picolinate (2.0 g, 9.2 mmol) was dissolved in dry DMF (15 mL), and N , N -diisopropylethylamine (4.1 mL, 23 mmol) was added at 0°C and di-tert-butyl dicarbonate (2.8 mL, 12 mmol), react at room temperature for 1.5 h, add water (20 mL), add dichloromethane for extraction (10 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, remove The solvent and the concentrated solution were separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 3/1) to obtain 1.98 g of a yellow liquid with a yield of 77%.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.01 (t, J = 8.1 Hz, 1H), 7.79 – 7.83 (m, 1H), 7.50 (t, J = 7.0 Hz, 1H), 4.50 – 4.55 (m, 2H), 4.45 – 4.50 (m, 2H), 1.42 – 1.47 (m, 12H).

MS (ESI, pos.ion) m/z: 281.25 [M+H] ⁺ .

Step 2: Synthesis of 6-(((tert-butoxycarbonyl)amino)methyl)picolinic acid

Ethyl 6-(((tert-butoxycarbonyl)amino)methyl)picolinate (700 mg, 2.5 mmol) and lithium hydroxide monohydrate (527 mg, 12.6 mmol) were added to tetrahydrofuran (5 mL) and water ( 5 mL) mixed solvent, the reaction was stopped after 1.5 h at 50 °C, diluted hydrochloric acid was added to adjust pH=6, extracted with ethyl acetate (10 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain a pale yellow oil The substance was 606 mg, and the yield was 96%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.06 (d, J = 7.6 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H) ), 4.44 (s, 2H), 1.48 (s, 9H).

MS (ESI, pos.ion) m/z: 253.10 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl ((6-(dimethylcarbamoyl)pyridin-2-yl)methyl)carbamate

6-(((tert-butoxycarbonyl)amino)methyl)picolinic acid (587-1-2) (600 mg, 2.38 mmol), dimethylamine hydrochloride (971 mg, 11.9 mmol), 1-ethyl Alkyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.3 g, 12 mmol) and N -hydroxy-7-azabenzotriazole (488 mg, 3.59 mmol) were dissolved in In dichloromethane (10 mL), N , N -diisopropylethylamine (2.4 mL, 15 mmol) was added dropwise to this solution at 0 °C, stirred at room temperature for 19 h, added with water (15 mL), followed by Dichloromethane extraction (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) , 554 mg of light yellow viscous solid was obtained with a yield of 83%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.78 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H) , 4.47 (d, J = 5.2 Hz, 2H), 3.16 (s, 3H), 3.07 (s, 3H), 1.48 (s, 9H).

MS (ESI, pos.ion) m/z: 280.30 [M+H] ⁺ .

Step 4: Synthesis of 6-(aminomethyl) -N , N -lutidylpyridinium dihydrochloride

Compound ((6-(dimethylaminocarbamoyl)pyridin-2-yl)methyl)carbamate tert-butyl ester (587-1-1) (550 mg, 1.97 mmol) was dissolved in methanol (5 mL) To the solution, 4 mol/L HCl in ethyl acetate solution (5 mL) was added, stirred at room temperature for 1 h, and the solvent was removed to obtain 486 mg of white solid with a yield of 97%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.02 (t, J = 7.8 Hz, 1H), 7.59 (t, J = 8.1 Hz, 2H), 4.37 (s, 2H), 3.16 (s , 3H), 3.07 (s, 3H).

MS (ESI, pos.ion) m/z: 180.15 [M+H-2HCl] ⁺ .

Intermediate 4: Intermediate (3-(aminomethyl)phenyl)carbamate hydrochloride

Step 1: Synthesis of compound N- (3-((tert-butoxycarbonylamino)methyl)phenyl)carbamate

The compound tert-butyl 3-aminobenzylcarbamate (503 mg, 2.26 mmol) was dissolved in dichloromethane (6 mL), methyl chloroformate (0.35 mL, 4.5 mmol) and N , N were added at 0°C -Diisopropylethylamine (1.2 mL, 7.3 mmol), the reaction was stopped after stirring at room temperature for 20 h, the organic phase was washed with an aqueous solution (10 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the concentrated solution was subjected to a silica gel column layer Separation (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) gave 511 mg of white solid with a yield of 90%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.26-7.32 (m, 3H), 7.01 (d, J = 6.9 Hz, 1H), 6.71 (br.s, 1H), 4.89 (br.s , 1H), 4.30 (d, J = 5.2 Hz, 2H), 3.79 (s, 3H), 1.48 (s, 9H).

MS (ESI, pos.ion) m/z: 303.10[M+Na] ⁺ .

Step 2: Synthesis of Compound (3-(aminomethyl)phenyl)carbamic acid methyl ester hydrochloride

Compound N- (3-((tert-butoxycarbonylamino)methyl)phenyl)carbamate (511 mg, 1.8 mmol) was dissolved in dichloromethane (2 mL) solution, and 4 mol/L HCl was added The ethyl acetate solution (3 mL) was stirred at room temperature for 1 h, and the solvent was removed to obtain 316 mg of a white solid with a yield of 96%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.79 (s, 1H), 8.48 (br.s, 2H), 7.56 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H ), 7.32 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 3.94 (s, 2H), 3.67 (s, 3H).

MS (ESI, pos.ion) m/z: 181.10 [M+H-HCl] ⁺ .

Intermediate 5: Intermediate (6-(1-methyl- 1H -pyrazol-4-yl)pyridin-2-yl)methanamine dihydrochloride

Step 1: Synthesis of compound ((6-bromopyridin-2-yl)methyl)carbamate tert-butyl ester

The compound (6-bromopyridin-2-yl)methanamine (1.0 g, 5.4 mmol) was dissolved in a solution of dichloromethane (15 mL), and N , N -diisopropylethylamine (3.0 mL, 18.0 mmol) was added. ), di-tert-butyl dicarbonate (1.5 mL, 6.5 mmol) was added at 0°C, stirred for 20 min, transferred to room temperature for 5 h, washed with water (50 mL), and then extracted with dichloromethane (5 mL × 3) , the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) to obtain a white solid 1.42 g, yield 92%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.73 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.48 (br.s, 1H), 7.30 (d, J = 7.5 Hz, 1H), 4.19 (d, J = 6.0 Hz, 2H), 1.40 (s, 9H).

MS (ESI, pos.ion) m/z: 233.10 [M-55] ⁺ .

Step 2: Synthesis of compound ((6-(1-methyl- 1H -pyrazol-4-yl)pyridin-2-yl)methyl)carbamate tert-butyl ester

Compound ((6-bromopyridin-2-yl)methyl)carbamic acid tert-butyl ester (298 mg, 1.0 mmol), (1-methyl- 1H -pyrazol-4-yl)boronic acid (153 mg, 1.2 mmol), sodium carbonate (332 mg, 3.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (42 mg, 0.06 mmol) were dissolved in anhydrous 1,4- Dioxane (6 mL) and water (2 mL), the air in the reaction flask was evacuated, nitrogen was introduced, the reaction was carried out at 100 ° C for 21 h, washed with water (50 mL), and then extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 196 mg of pale yellow liquid, The yield is 66%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.25 (s, 1H), 7.97 (s, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.41 (br.s, 1H), 7.04 (d, J = 7.6 Hz, 1H), 4.22 (d, J = 5.9 Hz, 2H), 3.88 (s, 3H), 1.42 (s, 9H) ).

MS (ESI, pos.ion) m/z: 289.25 [M+H] ⁺ .

Step 3: Synthesis of compound (6-(1-methyl- 1H -pyrazol-4-yl)pyridin-2-yl)methanamine dihydrochloride

Compound ((6-(1-methyl- 1H -pyrazol-4-yl)pyridin-2-yl)methyl)carbamate (186 mg, 0.64 mmol) was dissolved in dichloromethane (2 mL) solution, 4 mol/L HCl in ethyl acetate solution (3 mL) was added, stirred at room temperature for 40 min, and the solvent was removed to obtain 116 mg of pale yellow solid with a yield of 95%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.52 (br.s, 2H), 8.47 (s, 1H), 8.20 (s, 1H), 7.87 (t, J = 7.8 Hz, 1H ), 7.67 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 4.14-4.26 (m, 2H), 3.90 (s, 3H).

MS (ESI, pos.ion) m/z: 189.20 [M+H-HCl] ⁺ .

Intermediate 6: Intermediate 6- (aminomethyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methyl acyl pyridine dihydrochloride

Step 1: Synthesis of compound 6-(((tert-butoxycarbonyl)amino)methyl)picolinate ethyl ester

Ethyl 6-(aminomethyl)picolinate (2.0 g, 9.2 mmol) was dissolved in anhydrous N , N -dimethylformamide (15 mL), and N , N -diisopropyl was added at 0°C Ethylamine (4.1 mL, 23 mmol) and di-tert-butyl dicarbonate (2.8 mL, 12 mmol), react at room temperature for 1.5 h, add water (20 mL), add dichloromethane for extraction (10 mL × 3), the organic phase After the combination, it was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column separation (eluent: petroleum ether/ethyl acetate (v/v) = 3/1) to obtain 1.98 g of a yellow liquid with a yield of 77%.

¹ H NMR (600 MHz, CDCl ₃ ) δ(ppm): 8.01 (t, J = 8.1 Hz, 1H), 7.79 – 7.83 (m, 1H), 7.50 (t, J = 7.0 Hz, 1H), 4.50 – 4.55 (m, 2H), 4.45 – 4.50 (m, 2H), 1.42 – 1.47 (m, 12H).

MS (ESI, pos.ion) m/z: 281.25 [M+H] ⁺ .

Step 2: Synthesis of compound 6-(((tert-butoxycarbonyl)amino)methyl)picolinic acid

Ethyl 6-(((tert-butoxycarbonyl)amino)methyl)picolinate (700 mg, 2.5 mmol) and lithium hydroxide monohydrate (527 mg, 12.6 mmol) were added to tetrahydrofuran (5 mL) and water ( 5 mL) mixed solvent, the reaction was stopped after 1.5 h at 50 °C, diluted hydrochloric acid was added to adjust pH=6, extracted with ethyl acetate (10 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain a pale yellow oil 606 mg of substance, with a hand rate of 96%.

¹ H NMR (400 MHz, CD ₃ OD) δ(ppm): 8.06 (d, J = 7.6 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H) ), 4.44 (s, 2H), 1.48 (s, 9H).

MS (ESI, pos.ion) m/z: 253.10 [M+H] ⁺ .

Step 3: Synthesis of compound ((6-((4,4-difluorocyclohexyl)(methyl)carbamoylamino)pyridin-2-yl)methyl)carbamic acid tert-butyl ester

6-(((tert-butoxycarbonyl)amino)methyl)picolinic acid (347 mg, 1.38 mmol), 4,4-difluoro- N -methylcyclohexylamine hydrochloride (387 mg, 2.08 mmol) , 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4 g, 7.3 mmol) and N -hydroxy-7-azabenzotriazole (382 mg, 2.81 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, added N , N -diisopropylethylamine (1.8 mL, 11.0 mmol), stirred at room temperature for 5 h, added water (35 mL), Extracted with dichloromethane (15 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 486 mg of white solid, yield 92%.

¹ H NMR (400 MHz, CDCl ₃ ) δ(ppm): 7.76 – 7.83 (m, 1H), 7.56 (d, J = 7.7 Hz, 0.5H), 7.46 (d, J = 7.7 Hz, 0.5H), 7.32 – 7.37 (m, 1H), 4.67 – 4.75 (m, 0.5H), 4.47 (d, J = 5.0 Hz, 2H), 3.81 – 3.90 (m, 0.5H), 3.04 (s, 1.5H), 2.89 (s, 1.5H), 2.11 – 2.28 (m, 3H), 1.86 – 2.07 (m, 5H), 1.48 (s, 9H).

MS (ESI, pos.ion) m/z: 384.60 [M+H] ⁺ .

Step 4: Compound 6- (aminomethyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine dihydrochloride Amides

Compound (tert-butyl ((6-((4,4-difluorocyclohexyl)(methyl)carbamoylamino)pyridin-2-yl)methyl)carbamate (486 mg, 1.27 mmol) was dissolved in methanol ( 5 mL) solution, 4 mol/L HCl in ethyl acetate solution (10 mL) was added, stirred at room temperature for 1.5 h, and concentrated under reduced pressure to obtain 423 mg of white solid with a yield of 93%.

¹ H NMR (400 MHz, CD ₃ OD) δ(ppm): 8.00 – 8.05 (m, 1H), 7.56 – 7.61 (m, 2H), 4.57 – 4.62 (m, 0.5H), 4.36 (s, 2H) , 3.59 – 3.67 (m, 0.5H), 3.03 (s, 1H), 2.91 (s, 2H), 2.04 – 2.24 (m, 4H), 1.90 – 1.98 (m, 4H).

MS (ESI, pos.ion) m/z: 284.10 [M+H-2HCl] ⁺ .

Intermediate 7: Intermediate 6- (aminomethyl) - N - (4- fluorophenyl) - N - methyl acyl pyridine dihydrochloride

Step 1: Synthesis of compound ((6-((4-fluorophenyl)(methyl)carbamoylamino)pyridin-2-yl)methyl)carbamate tert-butyl ester

6-(((tert-butoxycarbonyl)amino)methyl)picolinic acid (236 mg, 0.94 mmol), 4-fluoro- N -methylaniline (182 mg, 1.45 mmol), 1-ethyl-(3 -Dimethylaminopropyl)carbodiimide hydrochloride (913 mg, 4.76 mmol) and N -hydroxy-7-azabenzotriazole (262 mg, 1.92 mmol) were dissolved in dichloromethane ( 10 mL), cooled to 0 °C, added N , N -diisopropylethylamine (0.96 mL, 5.80 mmol), stirred at room temperature for 5 h, added water (15 mL), and extracted with dichloromethane (10 mL). × 3), the organic phase was dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 287 mg of pale yellow oil, Yield 85%.

¹ H NMR (400 MHz, CDCl ₃ ) δ(ppm): 7.64 – 7.67 (m, 1H), 7.57 – 7.58 (m, 1H), 7.06 – 7.13 (m, 3H), 6.93 – 6.98 (m, 2H) , 4.21 (s, 2H), 3.52 (s, 3H), 1.51 (s, 9H).

MS (ESI, pos.ion) m/z: 360.10 [M+H] ⁺ .

Step 2: Compound 6- (aminomethyl) - N - (4- fluorophenyl) - N - methylpyridine dihydrochloride Amides

Compound (tert-butyl ((6-((4-fluorophenyl)(methyl)carbamoylamino)pyridin-2-yl)methyl)carbamate (260 mg, 1.97 mmol) was dissolved in methanol (5 mL) To the solution, 4 mol/L HCl in ethyl acetate solution (10 mL) was added, stirred at room temperature for 1.5 h, and concentrated under reduced pressure to obtain 184 mg of a light yellow viscous solid with a yield of 93%.

¹ H NMR (400 MHz, CD ₃ OD) δ(ppm): 7.73 – 7.78 (m, 1H), 7.38 – 7.40 (m, 1H), 7.30 – 7.32 (m, 1H), 7.22 – 7.29 (m, 2H) ), 7.00 – 7.04 (m, 2H), 4.21 (s, 2H), 3.50 (s, 3H).

MS (ESI, pos.ion) m/z: 260.10 [M+H-2HCl] ⁺ .

Intermediate 8: Intermediate N - (5- bromo-2- (difluoromethoxy) -4- (acyl methanesulfonamide) phenyl) - N - (cyclopropylmethyl) hydroxylamine

Step 1: Synthesis of compound 4-bromo-1-(difluoromethoxy)-2-nitrobenzene

The compound 4-bromo-2-nitrophenol (3.0 g, 14 mmol) was dissolved in N , N -dimethylformamide (15 mL), sodium difluorochloroacetate (3.8 g, 25 mmol) and carbonic acid were added. Cesium (8.1 g, 25 mmol), the reaction was stopped at 120 °C for 2 h, water (25 mL) was added, extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column Chromatographic separation (eluent: petroleum ether/ethyl acetate (v/v) = 5/1) gave 1.6 g of a light red liquid with a yield of 43%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.09 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.8, 2.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.63 (t, J _FH = 72.5 Hz, 1H).

MS (ESI, pos.ion) m/z: 267.00 [M].

Step 2: Synthesis of compound N- (5-bromo-2-(difluoromethoxy)phenyl)hydroxylamine

Compound 4-bromo-1-(difluoromethoxy)-2-nitrobenzene (1.6 g, 6 mmol), ammonium chloride (961 mg, 18 mmol) was dissolved in 1,4-dioxane ( 20 mL) and water (10 mL), zinc powder (1.2 g, 18 mmol) was added to the ice bath, the reaction was carried out at room temperature for 4 h, the solid was removed by filtration, the filtrate was concentrated, and extracted with ethyl acetate (50 mL × 3), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 15/1) to obtain 648 mg of pale yellow liquid, Yield 46%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.49 (d, J = 2.2 Hz, 1H), 7.14 (br.s, 1H), 7.06 (dd, J = 8.6, 2.3 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 5.34 (d, J = 1.8 Hz, 1H).

MS (ESI, pos.ion) m/z: 254.10 [M+H] ⁺ .

Step 3: Compound N - (5- bromo-2- (difluoromethoxy) phenyl) - N - Synthesis of (cyclopropylmethyl) hydroxylamine

Compound N- (5-bromo-2-(difluoromethoxy)phenyl)hydroxylamine (284 mg, 1.12 mmol), cyclopropylcarbaldehyde (250 mg, 3.57 mmol) was dissolved in ethanol (5 mL) and acetic acid (358 mg, 5.97 mmol) in a mixed solvent, sodium cyanoborohydride (374 mg, 3.95 mmol) was added, reacted at room temperature for 12 h, concentrated, added with water (10 mL), and extracted with ethyl acetate (5 mL × 3 ), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 20/1) to obtain 243 mg of a yellow-brown solid, the product rate of 69%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.74 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 8.5, 2.3 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.51 (t, J _FH = 74.7 Hz, 1H), 5.87 (s, 1H), 3.03 (d, J = 6.9 Hz, 1H), 1.12 – 1.22 (m, 1H), 0.51 – 0.56 (m, 2H), 0.24 – 0.28 (m, 2H).

MS (ESI, pos.ion) m/z: 308.05 [M+H] ⁺ .

Step 4: The compound N - (5- bromo-2- (difluoromethoxy) -4- (acyl methanesulfonamide) phenyl) - N - (cyclopropylmethyl) hydroxylamine Synthesis of

The compound N - (5- bromo-2- (difluoromethoxy) phenyl) - N - (cyclopropylmethyl) hydroxylamine (300 mg, 1.06 mmol) was dissolved in dichloromethane (6 mL), N , N -diisopropylethylamine (1.0 mL, 6.10 mmol) was added, methanesulfonic acid chloride (354 mg, 3.09 mmol) was added dropwise at 0 °C, the mixture was stirred at room temperature for 3 h, and then stopped, and water (15 mL) was added. , extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 8/ 1), 121 mg of light brown liquid was obtained, and the yield was 31%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.16 (s, 1H), 6.82 (s, 1H), 6.51 (t, J _FH = 73.3 Hz, 1H), 4.41 (br.s, 1H) , 3.23 (s, 1H), 2.96 – 2.99 (m, 1H), 1.10 – 1.16 (m, 1H), 0.61 – 0.65 (m, 2H), 0.27 – 0.31 (m, 2H).

MS (ESI, pos.ion) m/z: 386.10 [M+H] ⁺ .

Intermediate 9: Intermediate 1-Cyclopropyl- N -methylmethanamine hydrochloride

Step 1: Synthesis of compound tert-butyl cyclopropylmethylcarbamate

The compound cyclopropylmethylamine (0.51 g, 7.11 mmol) was dissolved in dichloromethane (15 mL) solution, N , N -diisopropylethylamine (3.5 mL, 21 mmol) was added, at -10 °C Di-tert-butyl dicarbonate (1.9 mL, 8.3 mmol) was added, stirred for 15 min, transferred to room temperature for 3 h, washed with water (50 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sulfuric acid The solution was dried over sodium, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 3/1) to obtain 810 mg of a colorless liquid with a yield of 67%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 6.84 (br.s, 1H), 2.80 (t, J = 6.1 Hz, 2H), 1.38 (s, 9H), 0.82-0.92(m , 1H), 0.34-0.38 (m, 2H), 0.09-0.14 (m, 2H).

MS (ESI, pos.ion) m/z: 116.25 [M-55] ⁺ .

Step 2: Synthesis of compound (cyclopropylmethyl)(methyl)carbamate tert-butyl ester

Sodium hydride (0.47 g, 11.9 mmol) was dissolved in N , N -dimethylformamide (15 mL) solution, and tert-butyl cyclopropylmethylcarbamate (0.81 g, 4.7 mmol) was added in an ice bath. ), iodomethane (0.5 mL, 8.0 mmol) was added after 5 min, the reaction was continued in an ice bath for 20 min, transferred to room temperature for 7 h, water (100 mL) was added, and extracted with ethyl acetate (25 mL × 3 ), the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 790 mg of pale yellow liquid with a yield of 90%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 3.04 (d, J = 6.9 Hz, 1H), 2.82 (s, 1H), 1.39 (s, 9H), 0.89-0.97 (m, 1H) ), 0.41-0.45 (m, 2H), 0.16-0.20 (m, 2H).

MS (ESI, pos.ion) m/z: 130.20 [M-55] ⁺ .

Step 3: Synthesis of compound 1-(cyclopropyl) -N -methylmethanamine hydrochloride

The compound (cyclopropylmethyl)(methyl)carbamate tert-butyl ester (0.79 g, 4.3 mmol) was dissolved in dichloromethane (6 mL) solution, and 4 mol/L HCl in ethyl acetate solution (8 mL), stirred at room temperature for 1.5 h, and removed the solvent to obtain 350 mg of pale yellow liquid with a yield of 97%.

¹ H NMR (400 MHz, DMSO- d ₆ ): δ (ppm) 2.74 (d, J = 7.4 Hz, 2H), 1.91 (s, 3H), 1.00-1.11 (m, 1H), 0.53-0.57 (m , 2H), 0.33-0.38 (m, 2H).

Intermediate 10: Intermediate 1-(2,4-Difluorophenyl) -N -methylmethanamine hydrochloride

Step 1: Synthesis of compound tert-butyl 2,4-difluorobenzylcarbamate

Compound 2,4-difluorophenylmethylamine (1.01 g, 7.1 mmol) was dissolved in dichloromethane (15 mL) solution, N , N -diisopropylethylamine (3.5 mL, 21 mmol) was added, Di-tert-butyl dicarbonate (2.0 mL, 8.7 mmol) was added at -10°C, stirred for 15 min, transferred to room temperature and reacted for 5 h, washed with water (50 mL), extracted with dichloromethane (5 mL × 3), The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 1.4 g of a colorless liquid, yield 82 %.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.31-7.39 (m, 2H), 7.15-7.20 (m, 1H), 7.06 (t, J = 8.0 Hz, 1H), 4.14 (d , J = 5.4 Hz, 2H), 1.39 (s, 9H).

MS (ESI, pos.ion) m/z: 266.15 [M+Na] ⁺ .

Step 2: Synthesis of compound (2,4-difluorobenzyl)(methyl)carbamate tert-butyl ester

Sodium hydride (0.63 g, 15.8 mmol) was dissolved in N , N -dimethylformamide (15 mL) solution, and tert-butyl 2,4-difluorobenzylcarbamate (1.4 g) was added at 0°C , 5.8 mmol), then add iodomethane (0.65 mL, 10.0 mmol) for 5 min, react at 0 °C for 20 min, transfer to room temperature for 12 h, add water (100 mL), extract with ethyl acetate (5 mL × 3 ), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 1.3 g of pale yellow liquid, The yield is 88%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.27-7.33 (m, 1H), 7.20-7.26 (m, 1H), 7.09 (t, J = 7.9 Hz, 1H), 4.39 (s , 2H), 2.78 (s, 3H), 1.38 (s, 9H).

MS (ESI, pos.ion) m/z: 280.20 [M+Na] ⁺ .

Step 3: Synthesis of compound 1-(2,4-difluorophenyl) -N -methylmethanamine hydrochloride

The compound (2,4-difluorobenzyl)(methyl)carbamate tert-butyl ester (1.3 g, 5.1 mmol) was dissolved in dichloromethane (6 mL) solution, and 4 mol/L HCl in ethyl acetate was added The solution (10 mL) was stirred at room temperature for 1 h, and the solvent was removed to obtain 763 mg of a pale yellow solid with a yield of 96%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.47-9.61 (m, 1H), 7.74-7.81 (m, 1H), 7.34-7.39 (m, 1H), 7.21 (t, J = 8.5 Hz, 1H), 4.13 (s, 2H), 2.54 (s, 2H), 2.51 (s, 1H).

MS (ESI, pos.ion) m/z: 158.20 [M+H-HCl] ⁺ .

Intermediate 11: Intermediate N -methyl-1-(pyridin-2-yl)methanamine dihydrochloride

Step 1: Synthesis of compound (pyridin-2-ylmethyl)carbamate tert-butyl ester

The compound 2-pyridylmethylamine (510 mg, 4.70 mmol) was dissolved in dichloromethane (15 mL) solution, N , N -diisopropylethylamine (2.3 mL, 14 mmol) was added, at -10 °C Di-tert-butyl dicarbonate (1.3 mL, 5.7 mmol) was added, stirred for 15 min, transferred to room temperature for 8 h, washed with water (50 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sulfuric acid The solution was dried over sodium, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 620 mg of a colorless liquid with a yield of 64%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.48 (d, J = 4.1 Hz, 1H), 7.76 (t, J = 7.3 Hz, 1H), 7.41 (br.s, 1H), 7.21-7.29 (m, 2H), 4.22 (d, J = 5.9 Hz, 2H), 1.41 (s, 9H).

MS (ESI, pos.ion) m/z: 209.10 [M+H] ⁺ .

Step 2: Synthesis of compound N -methyl-(pyridin-2-ylmethyl)carbamate tert-butyl ester

Sodium hydride (310 mg, 7.6 mmol) was dissolved in N , N -dimethylformamide (10 mL) solution, and tert-butyl (pyridin-2-ylmethyl)carbamate (620 °C) was added at 0 °C. mg, 2.98 mmol), then add iodomethane (0.3 mL, 5.0 mmol) for 5 min, react at 0 °C for 20 min, transfer to room temperature and react for 18 h, add water (100 mL), and extract with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 580 mg of pale yellow liquid, The yield is 88%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.52 (d, J = 4.3 Hz, 1H), 7.78 (t, J = 7.4 Hz, 1H), 7.26 – 7.29 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 4.45 (s, 2H), 2.86 (s, 3H), 1.43 (s, 4H), 1.30 (s, 5H).

MS (ESI, pos.ion) m/z: 223.25 [M+H] ⁺ .

Step 3: Synthesis of compound N -methyl-1-(pyridin-2-yl)methanamine dihydrochloride

The compound methyl(pyridin-2-ylmethyl)carbamate tert-butyl ester (580 mg, 2.6 mmol) was dissolved in dichloromethane (6 mL) solution, and 4 mol/L HCl in ethyl acetate solution (8 mL), stirred at room temperature for 1 h, and removed the solvent to obtain 310 mg of a gray solid with a yield of 98%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.69 (d, J = 4.4 Hz, 1H), 8.02 (t, J = 6.8 Hz, 1H), 7.68 – 7.70 (m, 1H), 7.52 – 7.55 (m, 1H), 4.33 (t, J = 5.5 Hz, 2H), 2.60 (t, J = 4.8 Hz, 2H).

MS (ESI, pos.ion) m/z: 123.30 [M+H] ⁺ .

Intermediate 12: Intermediate N - ((6- (aminomethyl) pyridin-2-yl) methyl) - N - (4,4- difluoro-cyclohexyl) as acetamide dihydrochloride

Step 1: Synthesis of compound ((6-(hydroxymethyl)pyridin-2-yl)methyl)carbamate tert-butyl ester

The compound 6-(((tert-butoxycarbonyl)amino)methyl)picolinate (747 mg, 2.67 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and lithium borohydride (304 mg, 14.0 mmol) was added under ice bath. ), the reaction was stopped after 2 h at room temperature, crushed ice was added, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (washed Removal agent: petroleum ether/ethyl acetate (v/v) = 1/2) to obtain 515 mg of white solid with a yield of 81%.

MS (ESI, pos.ion) m/z: 239.30 [M+H] ⁺ .

Step 2: Synthesis of compound ((6-carboxypyridin-2-yl)methyl)carbamic acid tert-butyl ester

Dimethyl sulfoxide (669 mg, 8.56 mmol) was dissolved in dichloromethane (2 mL), and a solution of oxalic chloride (1.1 g, 8.70 mmol) in dichloromethane (3 mL) was added at -78°C, where After reacting for 30 min at the temperature, a dichloromethane solution (10 mL) of the compound ((6-(hydroxymethyl)pyridin-2-yl)methyl)carbamate (510 mg, 2.14 mmol) in dichloromethane (10 mL) was added, and the reaction was continued. For 30 min, triethylamine (1.5 mL, 11 mmol) was added at -78°C, the temperature was slowly raised to room temperature, the organic phase was washed with water (10 mL × 3 ), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the solution was concentrated. Separation by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 3/1) gave 459 mg of white solid with a yield of 90%.

MS (ESI, pos.ion) m/z: 237.10 [M+H] ⁺ .

Step 3: Synthesis of compound ((6-(((4,4-difluorocyclohexyl)amino)methyl)pyridin-2-yl)methyl)carbamic acid tert-butyl ester

Compound ((6-carbamoylpyridin-2-yl)methyl)carbamate tert-butyl ester (233 mg, 0.99 mmol) and 4,4-difluorocyclohexylamine hydrochloride (217 mg, 1.26 mmol) Dissolve in ethanol (5 mL), add acetic acid (59 mg, 0.98 mmol) and sodium cyanoborohydride (187 mg, 2.98 mmol), react at 50 °C for 6 h, remove ethanol under reduced pressure, wash with water (10 mL), Ethyl acetate extraction (10 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/5 ) to obtain 323 mg of a colorless liquid with a yield of 92%.

MS (ESI, pos.ion) m/z: 356.25 [M+H] ⁺ .

Step 4: Synthesis of compound ((6-(( N- (4,4-difluorocyclohexyl)acetamido)methyl)pyridin-2-yl)methyl)carbamate tert-butyl ester

Compound ((6-(((4,4-difluorocyclohexyl)amino)methyl)pyridin-2-yl)methyl)carbamate (322 mg, 0.91 mmol) was dissolved in dichloromethane ( 8 mL), N , N -diisopropylethylamine (0.75 mL, 4.5 mmol) was added, acetyl chloride (0.2 mL, 3.0 mmol) was added dropwise at 0 °C, the reaction was stopped after stirring at room temperature for 5 h, Water (20 mL) was added, extracted with dichloromethane (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain 212 mg of white solid with a yield of 59%.

MS (ESI, pos.ion) m/z: 398.30 [M+H] ⁺ .

Step 5: The compound N - ((6- (aminomethyl) pyridin-2-yl) methyl) - N - Synthesis of (4,4-difluoro-cyclohexyl) as acetamide dihydrochloride

Compound ((6-(( N- (4,4-difluorocyclohexyl)acetamido)methyl)pyridin-2-yl)methyl)carbamic acid tert-butyl ester (200 mg, 0.5 mmol) was dissolved in Dichloromethane (4 mL) solution was added with 4 mol/L HCl in ethyl acetate solution (6 mL), stirred at room temperature for 30 min, and the solvent was removed to obtain 182 mg of white solid with a yield of 97%.

MS (ESI, pos.ion) m/z: 298.30 [M+H-HCl] ⁺ .

Intermediate 13: 6-(Aminomethyl)-2-methylisoindolin-1-one

Step 1: Synthesis of methyl 3-oxoisoindoline-5-carboxylate

The compound 3-oxoisoindoline-5-carboxylic acid (1.00 g, 5.60 mmol), N , N' -carbonyldiimidazole (960 mg, 5.92 mmol) was dissolved in N , N' -dimethylformamide (20 mL), stirred at 60 °C for 30 min, then added N , N -diisopropylethylamine (1.90 mL, 11.0 mmol) and methanol (0.50 mL, 11.0 mmol), and stirred at 60 °C for 3.5 h. The solvent was removed by concentration under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain a pale yellow solid (900 mg, yield 83%).

¹ H NMR (400 MHz, DMSO- d ₆ ): δ (ppm) 8.15 – 8.18 (m, 1H), 7.95 (s, 2H), 4.47 (s, 2H), 3.89 (s, 3H).

MS (ESI, pos.ion) m/z: 192.10 [M+H] ⁺ .

Step 2: Synthesis of methyl 2-methyl-3-oxoisoindoline-5-carboxylate

Compound 3-oxoisoindoline-5-carboxylic acid methyl ester (1.00 g, 5.23 mmol), sodium hydride (271 mg, 6.78 mmol) was dissolved in N , N' -dimethylformamide (40 mL) was stirred at 50 °C for 20 min under nitrogen atmosphere, dimethyl sulfate (866 mg, 6.79 mmol) was added, the temperature was raised to 100 °C and the reaction was stirred for 2 h. The reaction was stopped, concentrated under reduced pressure to remove the solvent, dissolved in ethyl acetate (40 mL), washed with water (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the concentrate was separated by silica gel column chromatography ( Eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to give a brown solid (450 mg, 42% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.50 (s, 1H), 8.20 – 8.26 (m, 1H), 7.51 (d, J = 7.9 Hz, 1H), 4.43 (s, 2H), 3.95 (s, 3H), 3.22 (s, 3H).

MS (ESI, pos.ion) m/z: 206.15 [M+H] ⁺ .

Step 3: Synthesis of 6-(hydroxymethyl)-2-methylisoindolin-1-one

The compound 2-methyl-3-oxoisoindoline-5-carboxylic acid methyl ester (460 mg, 2.24 mmol) was dissolved in tetrahydrofuran (25 mL), and lithium borohydride (195 mg, 8.95 mmol) was added , stirred at 50°C for 6 h, stopped the reaction, added water (10 mL), stirred for 5 min, concentrated under reduced pressure to remove the solvent, and separated the concentrate by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 10/1) to give a white solid (370 mg, 93% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.76 (s, 1H), 7.57 – 7.64 (m, 1H), 7.51 – 7.56 (m, 1H), 4.71 (s, 2H), 4.49 ( s, 2H), 3.21 (s, 3H).

MS (ESI, pos.ion) m/z: 178.20 [M+H] ⁺ .

Step 4: Synthesis of (2-methyl-3-oxoisoindolin-5-yl)methyl mesylate

Compound 6-(hydroxymethyl)-2-methylisoindol-1-one (252 mg, 1.42 mmol) was dissolved in dichloromethane (10 mL), and N , N -diisopropylethylamine was added (737 mg, 0.94 mmol), stirred under ice bath for 5 min, added methanesulfonic acid chloride (325 mg, 2.84 mmol), stirred at room temperature for 1 h, stopped the reaction, added water (10 mL), stirred for 5 min, reduced pressure The solvent was removed by concentration, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain a pale yellow solid (240 mg, yield 66%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.87 (s, 1H), 7.57 – 7.63 (m, 1H), 7.46 – 7.52 (m, 1H), 5.31 (s, 2H), 4.40 (s , 2H), 3.21 (s, 3H), 2.98 (s, 3H).

MS (ESI, pos.ion) m/z: 256.15 [M+H] ⁺ .

Step 5: Synthesis of 6-(azidomethyl)-2-methylisoindolin-1-one

Compound (2-methyl-3-oxoisoindolin-5-yl)methylmethanesulfonate (240 mg, 0.94 mmol) and sodium azide (305 mg, 4.69 mmol) were dissolved in N , N' -dimethylformamide (10 mL), stirred at 80 °C for 2.5 h, concentrated under reduced pressure to remove the solvent, dissolved in ethyl acetate (20 mL), washed with water (10 mL × 2), and the organic phase was washed with anhydrous Dry over sodium sulfate and concentrate under reduced pressure to give a pale yellow solid (181 mg, 95% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.79 (s, 1H), 7.43 – 7.53 (m, 2H), 4.43 (s, 2H), 4.39 (s, 2H), 3.21 (s, 3H) ).

MS (ESI, pos.ion) m/z: 203.15 [M+H] ⁺ .

Step 6: Synthesis of 6-(aminomethyl)-2-methylisoindolin-1-one

Compound 6-(azidomethyl)-2-methylisoindolin-1-one (180 mg, 0.89 mmol) was dissolved in methanol (10 mL), Pd/C (20 mg, 0.10 g/ g), pass into hydrogen, stir for 30 min at room temperature, remove the catalyst through diatomaceous earth suction filtration, concentrate under reduced pressure to remove the solvent, and separate the concentrate by silica gel column chromatography (eluent: dichloromethane/methanol (v/ v) = 10/1) to give a white solid (67 mg, 42%).

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.73 (s, 1H), 7.27 – 7.63 (m, 1H), 7.50 – 7.56 (m, 1H), 4.48 (s, 2H), 3.93 ( s, 2H), 3.19 (s, 3H).

MS (ESI, pos.ion) m/z: 177.20 [M+H] ⁺ .

Intermediate 14: 5-(Aminomethyl)-2-methylisoindolin-1-one

Step 1: Synthesis of methyl 1-oxoisoindoline-5-carboxylate

Compound 1-oxoisoindoline-5-carboxylic acid (2.00 g, 11.0 mmol), N , N' -carbonyldiimidazole (2.00 g, 12.0 mmol) was dissolved in N , N' -dimethylformamide (40 mL), stirred at 60 °C for 30 min, added N , N -diisopropylethylamine (7.50 mL, 45.0 mmol) and methanol (1.80 mL, 45.0 mmol) successively, and stirred at 60 °C for 3.5 h. The solvent was removed by concentration under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain a pale yellow solid (1.00 g, yield 46%).

¹ H NMR (600 MHz, DMSO- d ₆ ): δ (ppm) 8.81 (s, 1H), 8.16 (s, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 4.44 (s, 2H), 3.89 (s, 3H).

MS (ESI, pos.ion) m/z: 192.20 [M+H] ⁺ .

Step 2: Synthesis of methyl 2-methyl-1-oxoisoindoline-5-carboxylate

Compound 1-oxoisoindoline-5-carboxylic acid methyl ester (945 mg, 4.94 mmol), sodium hydride (300 mg, 7.50 mmol) was dissolved in N , N' -dimethylformamide (30 mL) was stirred at 50 °C for 20 min under nitrogen atmosphere, dimethyl sulfate (944 mg, 7.41 mmol) was added, the temperature was raised to 100 °C and the reaction was stirred for 2 h. The reaction was stopped, concentrated under reduced pressure to remove the solvent, dissolved in ethyl acetate (20 mL), washed with water (10 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the concentrate was separated by silica gel column chromatography (eluting Reagent: petroleum ether/ethyl acetate (v/v) = 1/4) to give a brown solid (600 mg, 59% yield).

¹ H NMR (600 MHz, CDCl3): δ (ppm) 8.14 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 4.43 (s, 2H) ), 3.95 (s, 3H), 3.22 (s, 3H).

MS (ESI, pos.ion) m/z: 206.20 [M+H] ⁺ .

Step 3: Synthesis of 5-(hydroxymethyl)-2-methylisoindol-1-one

The compound 2-methyl-1-oxoisoindoline-5-carboxylic acid methyl ester (600 mg, 2.92 mmol) was dissolved in tetrahydrofuran (25 mL), lithium borohydride (254 mg, 11.7 mmol) was added, Stir at 50°C for 5 h, stop the reaction, add water (10 mL), stir for 5 min, concentrate under reduced pressure to remove the solvent, and separate the concentrate by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20 /1) to give a white solid (437 mg, 84%).

¹ H NMR (600 MHz, CDCl ₃ ): δ (ppm) 7.76 (d, J = 7.8 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J = 7.7 Hz, 1H), 4.76 – 4.83 ( m, 2H), 4.34 (s, 2H), 3.18 (s, 3H).

MS (ESI, pos.ion) m/z: 178.20 [M+H] ⁺ .

Step 4: Synthesis of (2-methyl-1-oxoisoindolin-5-yl)methylmethanesulfonate

The compound 5-(hydroxymethyl)-2-methylisoindol-1-one (250 mg, 1.41 mmol) was dissolved in dichloromethane (10 mL), and N , N -diisopropenylacetone was added Amine (732 mg, 5.64 mmol), stirred under ice bath for 5 min, added methanesulfonic acid chloride (326 mg, 2.84 mmol), stirred at room temperature for 1 h, stopped the reaction, added water (10 mL), stirred for 5 min, reduced The solvent was removed by pressure concentration, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain a white solid (250 mg, yield 69%).

Compound 206-4: ¹ H NMR (600 MHz, CDCl ₃ ): δ (ppm) 7.86 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H) , 5.31 (s, 2H), 4.40 (s, 2H), 3.21 (s, 3H), 2.99 (s, 3H).

MS (ESI, pos.ion) m/z: 256.15 [M+H] ⁺ .

Step 5: Synthesis of 5-(azidomethyl)-2-methylisoindolin-1-one

Compound (2-methyl-1-oxoisoindolin-5-yl)methylmethanesulfonate (250 mg, 0.98 mmol) and sodium azide (318 mg, 4.89 mmol) were dissolved in N , N' -dimethylformamide (10 mL), stirred at 80 °C for 3 h, concentrated under reduced pressure to remove the solvent, dissolved in ethyl acetate (20 mL), washed with water (10 mL × 2), and the organic phase was washed with anhydrous It was dried over sodium sulfate and concentrated under reduced pressure to remove the solvent to give a pale yellow solid (198 mg, 100% yield).

¹ H NMR (600 MHz, CDCl ₃ ): δ (ppm) 7.84 (d, J = 7.7 Hz, 1H), 7.37 – 7.43 (m, 2H), 4.45 (s, 2H), 4.39 (s, 2H), 3.20 (s, 3H).

MS (ESI, pos.ion) m/z: 203.20 [M+H] ⁺ .

Step 6: Synthesis of 5-(aminomethyl)-2-methylisoindolin-1-one

Compound 5-(azidomethyl)-2-methylisoindolin-1-one (206-5) (198 mg, 0.98 mmol) was dissolved in methanol (10 ml), Pd/C (30 mg, 0.10 g/g), pass through hydrogen, stir at room temperature for 30 min, remove the catalyst through diatomaceous earth suction filtration, concentrate under reduced pressure to remove the solvent, and separate the concentrate by silica gel column chromatography (eluent: dichloromethane) /methanol (v/v) = 10/1) to give a white solid (84 mg, 49%).

¹ H NMR (600 MHz, CD ₃ OD): δ (ppm) 7.71 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 4.48 (s , 2H), 3.92 (s, 2H), 3.19 (s, 3H).

MS (ESI, pos.ion) m/z: 177.20 [M+H] ⁺ .

Intermediate 15: 6- (hydroxymethyl) - N - (p-tolyl) pyridine Amides

Step 1: Synthesis of compound 6-(p-toluylcarbamoyl) picolinate methyl ester

Compound 6-(methoxycarbonyl)picolinic acid (2.00 g, 11 mol), p-toluidine (1.42 g, 13.3 mmol) were dissolved in dichloromethane (50 mL) solution, 1-hydroxy-7-azo was added Benzotriazole (HOAT) (2.30 g, 16.9 mmol), cooled at 0 °C, then added N , N -diisopropylethylamine (DIPEA) (4.3 g, 33.3 mmol), 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (4.2 g, 21.9 mmol), transferred to room temperature and stirred for 17 h. The reaction was stopped by adding water, extracted with dichloromethane (100 mL × 3), the organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/ v) = 4/1) to give a pale yellow solid (2.37 g, 79.40 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.97 (s, 1H), 8.49 (dd, J = 7.8, 1.1 Hz, 1H), 8.26 (dd, J = 7.7, 1.1 Hz, 1H), 8.06 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.20 (d, J =8.2Hz, 2H), 4.05 (s, 3H), 2.35 (s, 3H).

MS (ESI, pos.ion) m/z: 271.10 [M+H] ⁺ .

Step 2: Compound 6- (hydroxymethyl) - N - Synthesis of (p-tolyl) pyridine Amides of

Compound 6-(p-toluylcarbamoyl)methyl picolinate (1.68 g, 6.22 mmol) was dissolved in dry tetrahydrofuran solution (15 mL), sodium borohydride (400 mg, 10.58 mmol) was added, and The reaction was stirred at room temperature for 24 h. Saturated brine (15 mL) and (20 mL) water were added to stop the reaction, extracted with ethyl acetate (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/EtOAc (v/v) = 3/2) to give a white solid (1.26 g, 84.70 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.77 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.91 (t, J = 7.7 Hz, 1H), 7.65 (d, J = 8.3 Hz , 2H), 7.54 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 4.88 (s, 2H), 2.83 (br.s, 1H), 2.35 (s, 3H) .

MS (ESI, pos.ion) m/z: 243.10 [M+H] ⁺ .

Intermediate 16: 6-(Hydroxymethyl) -N -picolinamide

Step 1: Synthesis of methyl 6-(methylcarbamoyl)picolinate

Compound 6-(methoxycarbonyl)picolinic acid (2.00 g, 11 mol), methylamine hydrochloride (2.3 g, 34.1 mmol) were dissolved in dichloromethane (50 mL) solution, 1-hydroxy-7-azo was added Benzotriazole (HOAT) (2.30 g, 16.9 mmol), cooled at 0 °C, then added N,N-diisopropylethylamine (DIPEA) (5.7 g, 44.1 mmol), 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (4.2 g, 21.9 mmol), transferred to room temperature and stirred for 9 h. The reaction was stopped by adding water, extracted with dichloromethane (100 mL × 2), the organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/EtOAc = 1 : 2 ) , a white solid (1.63 g, 76.00 % yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (dd, J = 7.8, 0.9 Hz, 1H), 8.22 (dd, J = 7.8, 1.0 Hz, 1H), 8.11 (br.s, 1H), 8.01 ( t, J = 7.8 Hz, 1H), 4.02 (s, 3H), 3.06 (d, J = 5.1 Hz, 3H).

MS (ESI, pos.ion) m/z: 195.10 [M+H] ⁺ .

Step 2: Synthesis of 6-(hydroxymethyl) -N-picolinamide

Compound 6-(methylcarbamoyl)picolinate (800 mg, 4.12 mmol) was dissolved in dry tetrahydrofuran (15 mL) solution, cooled at 0 °C, and lithium borohydride (230 mg, 10.56 mmol) was added. mmol), and then transferred to room temperature and stirred for 1 h. Saturated brine (15 mL) was added and stirred to stop the reaction, extracted with ethyl acetate (20 mL×3), the organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: Petroleum ether/EtOAc = 3:7) to give a white solid (610 mg, 89.10% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J = 7.7 Hz, 1H), 7.96 (br.s, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 4.81 (s, 2H), 3.12 (br.s, 1H), 3.04 (d, J = 5.1 Hz, 3H).

MS (ESI, pos.ion) m/z: 167.20 [M+H] ⁺ .

Intermediate 17: tert-Butyl 6-(hydroxymethyl)picolinate

Step 1: Synthesis of 2-tert-butyl 6-methylpyridine-2,6-dicarboxylate

Compound 6-(methoxycarbonyl)picolinic acid (500 mg, 2.76 mmol) was dissolved in tetrahydrofuran (10 mL) solvent, nitrogen was replaced three times, and tertiary N , N' -diisopropylcarbamate was added under nitrogen atmosphere Butyl ester (600 mg, 2.99 mmol), after the raw material was added, was transferred to 60 °C and stirred for 3 h. Concentrate under reduced pressure to remove the tetrahydrofuran solvent, add dichloromethane (10 mL) to dissolve the solvent, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1) , the product was obtained as a white solid (190 mg, 29.01 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.97 (t, J = 7.8 Hz, 1H), 4.01 (s , 3H), 1.65 (s, 9H).

MS (ESI, pos.ion) m/z: 182.15 [M+H] ⁺ .

Step 2: Synthesis of tert-butyl 6-(hydroxymethyl)picolinate

Compound 2-tert-butyl 6-methylpyridine-2,6-dicarboxylate (190 mg, 0.80 mmol) was dissolved in dry tetrahydrofuran (10 mL) solvent, and sodium borohydride (99 mg, 2.62 mmol) was added. ), and the reaction was stirred at room temperature for 2.5 h. Saturated brine (20 mL) was added and stirred to stop the reaction, extracted with ethyl acetate (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: Petroleum ether/ethyl acetate (v/v)=3/7) to give a white solid (60 mg, 35.81 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 7.7 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 4.84 (s , 2H), 3.92 (br.s, 1H), 1.63 (s, 9H).

MS (ESI, pos.ion) m/z: 210.15 [M+H] ⁺ .

Intermediate 18: 6- (hydroxymethyl) - N - (4- hydroxyphenyl) - N - methylpyridine Amides

Step 1: Synthesis of compound 6-((4-hydroxyphenyl)(methyl)carbamoyl)picolinate methyl ester

Compound 6-(methoxycarbonyl)picolinic acid (1.00 g, 5.52 mmol), p-methylaminophenol (820 mg, 6.62 mmol) were dissolved in DMF (15 ml) solution, 2-(7-azobenzoic acid was added) triazole) -N , N , N' , N' -tetramethylurea hexafluorophosphate (HATU) (3.15 g, 8.28 mmol), cooled at 0 °C, and added N , N -diisopropyl Ethylamine (DIPEA) (1.28 g, 9.94 mmol), transferred to room temperature and stirred for 1 h. The reaction was stopped by adding water, extracted with ethyl acetate (10 mL × 4), the organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v)=1/4) , a light brown liquid (1.2 g, 76 % yield) was obtained.

¹ H NMR (400 MHz, DMSO- d ₆ ) 9.49 (br.s, 1H), 7.90 – 7.83 (m, 2H), 7.54 – 7.48 (m, 1H), 6.95 (d, J = 8.5 Hz, 2H) , 6.55 (d, J = 8.5 Hz, 2H), 3.84 (s, 3H), 3.34 (s, 3H).

MS (ESI, pos.ion) m/z: 287.10 [M+H] ⁺ .

Step 2: Compound 6- (hydroxymethyl) - N - (4- hydroxyphenyl) - N - Synthesis of Amides methylpyridine

The compound, methyl 6-((4-hydroxyphenyl)(methyl)carbamoyl)picolinate (1.20 g, 4.19 mmol) was dissolved in dry tetrahydrofuran solution (15 mL) and sodium borohydride was added (480 mg, 12.57 mmol), the reaction was stopped by stirring at room temperature for 13 h, dilute hydrochloric acid was added to adjust pH=6, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH/DCM(v/v)=1:25) , a pale yellow solid (604 mg, 56%) was obtained.

¹ H NMR (400 MHz, DMSO- d ₆ ) 9.44 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H), 6.91 (d, J = 8.0 Hz, 2H), 6.55 (d, J = 7.9 Hz, 2H), 5.33 (s, 1H), 4.33 (d, J = 4.9 Hz, 2H), 3.30 ( s, 3H).

MS (ESI, pos.ion) m/z: 259.20 [M+H] ⁺ .

Example

Example 1: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (2,4- Difluorobenzyl)pyrrolidine-2-carboxamide

Step 1: Compound (R) -1- tert-butyl 2-methyl 4 - (((trifluoromethyl) sulfonyl acyl) oxy) -1 H - pyrrole -1,2 (2 H, 5 H) - Synthesis of dicarboxylates

Compound Boc-4-oxo-D-proline methyl ester (0.98 g, 4.0 mmol) was dissolved in dichloromethane (15 mL) solution, and N , N -diisopropylethylamine was added at -15°C (3.4 mL, 20.5 mmol), trifluoromethanesulfonic anhydride (1.3 mL, 7.7 mmol), stirred at -15 °C for 10 min, transferred to room temperature and reacted for 18 h, stopped the reaction, added water (50 mL), mixed with 2 Extracted with methyl chloride (5 mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 6/1) to obtain yellow oil 1.3 g, 86% yield.

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, pos.ion) m/z: 398.10 [M+Na] ⁺ .

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

The compound (R) -1- tert-butyl 2-methyl 4 - (((trifluoromethyl) sulfonyl acyl) oxy) -1 H - pyrrole -1,2 (2 H, 5 H) - two Carboxylic acid ester (1.3 g, 3.5 mmol), pinacol diboronate (1.3 g, 5.1 mmol), potassium acetate (1.1 g, 11.2 mmol) and [1,1'-bis(diphenylphosphino)di Ferrocene] palladium dichloride (130 mg, 0.2 mmol) was mixed in dry 1,4-dioxane (30 mL) solution, reacted at 100 °C for 13 h under nitrogen protection, cooled to room temperature, and the reaction solution was pumped up filter, add 50 mL of water to the filtrate, extract with ethyl acetate (5 mL × 3), combine the organic phases and dry with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: petroleum ether/acetic acid). Ethyl ester (v/v) = 6/1) to obtain light red liquid 1.05 g, yield 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, pos.ion) m/z: 376.15 [M+Na] ⁺ .

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

The compound (R) -1- tert-butyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H - Pyrrole-1,2( 2H , 5H )-dicarboxylate (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 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (120 mg, 0.16 mmol) were mixed on dry In a solution of 1,4-dioxane (15 mL), the reaction was carried out at 100 °C for 3 h under nitrogen protection, the reaction solution was suction filtered, 50 mL of water was added to the filtrate, and then extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 8/1) to obtain 1.13 g of a light red liquid, with a yield of 1.13 g. 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, pos.ion) m/z: 462.20 [M+Na] ⁺ .

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

The compound (R) -1- tert-butyl 2-methyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -1 H - pyrrole-1,2 ( 2H , 5H )-dicarboxylate (1.1 g, 2.5 mmol) was dissolved in methanol (15 mL), Pd/C (260 mg, 10%) was added, and hydrogen was passed through to react at room temperature for 7 h, and then the The reaction solution was suction filtered, and the filtrate was concentrated to obtain 990 mg of 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, pos.ion) m/z: 464.25 [M+Na] ⁺ .

Step 5: Synthesis of compound (2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride

The compound ( 2R )-1-tert-butyl-2-methyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2 -Dicarboxylate (990 mg, 2.2 mmol) was dissolved in dichloromethane (6 mL) solution, 4 mol/L HCl in ethyl acetate solution (8 mL) was added, stirred at room temperature for 50 min, and the solvent was removed to obtain White solid 751 mg, yield 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, pos.ion) m/z: 342.20 [M+H-HCl] ⁺ .

Step 6: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester Synthesis

Compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride (203 mg, 0.6 mmol) was dissolved in dichloromethane (5 mL), N , N -diisopropylethylamine (0.2 mL, 1.0 mmol) and acetyl chloride (0.1 mL, 1.0 mmol) were added dropwise at 0 °C, room temperature The reaction was stopped after stirring for 5 h, the organic phase was washed with aqueous solution (10 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v ) = 1/1), 186 mg of light yellow liquid was obtained, and the yield was 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, pos.ion) m/z: 384.20 [M+H] ⁺ .

Step 7: Synthesis of compound (2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester (426 mg, 1.1 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (4 mL), then lithium hydroxide monohydrate (203 mg, 4.8 mmol) was added, the reaction was stopped after 3 h at 50 °C, and hydrochloric acid was added to adjust the solution pH=1, then extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 388 mg of a colorless liquid with a yield of 95%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.12 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.878-6.93 (m, 1H), 6.74 (t, J _FH = 74.9 Hz, 1H), 4.43 – 4.47 (m, 1H), 4.08 – 4.15 (m, 1H), 3.94 (d, J = 6.8 Hz, 2H), 3.50 – 3.64 (m, 2H) , 2.72 – 2.78 (m, 1H), 2.09 (s, 3H), 2.00 – 2.08 (m, 1H), 1.27-1.36 (m, 1H), 0.63-0.67 (m, 2H), 0.37-0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 370.25 [M+H] ⁺ .

Step 8: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (2,4-di Synthesis of Fluorobenzyl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (123 mg, 0.33 mmol), (2,4-difluorophenyl)methanamine (96 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.83 mmol) and N -hydroxy-7-azabenzotriazole (82 mg, 0.60 mmol) were dissolved in dichloromethane (6 mL), to this solution was added dropwise N , N at 0 °C -Diisopropylethylamine (0.4 mL, 2.0 mmol), stir at room temperature for 21 h, add water (15 mL), extract with dichloromethane (5 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, reduce It was concentrated under pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) to obtain 113 mg of white solid with a yield of 68%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.46-7.52 (m, 1H), 7.08-7.12 (m, 2H), 6.93-6.97 (m, 3H), 6.74 (t, J _FH = 75.7 Hz, 1H), 4.44-4.49 (m, 3H), 4.05-4.11 (m, 1H), 3.93 (d, J = 6.8 Hz, 2H), 3.61-3.66 (m, 1H), 3.44-3.53 (m , 1H), 2.61-2.68 (m, 1H), 2.14 (s, 3H), 2.00-2.09 (m, 1H), 1.27-1.35 (m, 1H), 0.62-0.67 (m, 2H), 0.37-0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 495.25 [M+H] ⁺ .

Example 2: Compound ( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (2,4- Difluorobenzyl)pyrrolidine-2-carboxamide

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

Compound Boc-4-oxo-L-proline methyl ester (5.0 g, 20.6 mmol) was dissolved in dichloromethane (100 mL) solution, cooled to -10 °C, and N,N -diisopropyl was added Ethylamine (17.0 mL, 103 mmol) was slowly added dropwise with trifluoromethanesulfonic anhydride (9.9 g, 35 mmol), transferred to room temperature for 16 h, water (100 mL) was added to quench the reaction, and the organic phase was separated after stirring for 10 min , dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1) to obtain 7.1 g of a light yellow oily product. rate of 92%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 5.70 – 5.74 (m, 1H), 5.00 – 5.02 (m, 1H), 4.28 – 4.36 (m, 2H), 3.75 – 3.77 (m, 3H) ,1.43 – 1.48 (m, 9H).

MS (ESI, pos.ion) m/z: 320.90 [M-55] ⁺ .

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

The compound (S) -1- tert-butyl 2-methyl 4 - (((trifluoromethyl) sulfonyl acyl) oxy) -1 H - pyrrole -1,2 (2 H, 5 H) - two Carboxylic acid ester (2.9 g, 7.7 mmol), pinacol diboronate (2.9 g, 11 mmol), potassium acetate (2.3 g, 23 mmol) and [1,1'-bis(diphenylphosphino)bis Ferrocene] palladium dichloride (50 mg, 0.068 mmol) was mixed in dry 1,4-dioxane (40 mL) solution, reacted at 100 °C for 5 h under nitrogen protection, cooled to room temperature, filtered, and the filtrate was concentrated , the residue was added with aqueous solution (30 mL) and ethyl acetate (50 mL), and the organic phase was separated after stirring evenly. The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: Petroleum ether/ethyl acetate (v/v) = 3/1) to obtain light brown liquid 1.44 g, yield 51%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 6.23 – 6.32 (m, 1H), 5.03 – 5.09 (m, 1H), 4.23 – 4.29 (m, 2H), 3.77 (s, 3H), 1.44 (s, 6H), 1.26 – 1.30 (m, 9H), 1.22 (s, 3H).

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

The compound (S) -1- tert-butyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H - Pyrrole-1,2( 2H , 5H )-dicarboxylate (886 mg, 3.2 mmol), 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (1.1 g, 3.2 mmol), potassium phosphate (2.7 g, 13 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (110 mg, 0.15 mmol) were mixed on dry In a solution of 1,4-dioxane (25 mL), reacted at 100 °C for 5 h under nitrogen protection, cooled to room temperature, concentrated, the residue was added with aqueous solution (20 mL) and ethyl acetate (30 mL), stirred well After separating the organic phase, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 3/1) to obtain light brown Liquid 576 mg, yield 41%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.12 – 7.15 (m, 1H), 6.93 – 6.96 (m, 2H), 6.63 (t, J _FH = 75.4 Hz, 1H), 5.99 – 6.02 ( m, 1H), 5.10 – 5.19 (m, 1H), 4.47 – 4.65 (m, 2H), 3.85 – 5.90 (m, 2H), 3.75 (s, 3H), 1.45 – 1.52 (m, 9H), 1.23- 1.33 (m, 1H), 0.63 – 0.67 (m, 2H), 0.33 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 462.10 [M+Na] ⁺ .

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

The compound (S) -1- tert-butyl 2-methyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) -1 H - pyrrole-1,2 ( 2H , 5H )-dicarboxylate (263 mg, 0.6 mmol) was added with methanol (8 mL) to dissolve, added with Pd/C (54 mg,), reacted with hydrogen at room temperature and pressure for 6 h, suction filtered, The filtrate was concentrated to obtain 258 mg of a colorless liquid with a yield of 97%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.10 (d, J = 7.9 Hz, 1H), 6.77 – 6.81 (m, 2H), 6.59 (t, J _FH = 75.6 Hz, 1H), 4.30 – 4.40 (m, 1H), 4.02 – 4.06 (m, 0.6H), 3.91 – 3.95 (m, 0.4H), 3.85 (t, J = 6.7 Hz, 2H), 3.75 – 3.77 (m, 3H), 3.38 – 3.44 (m, 1H), 3.27 – 3.36 (m, 1H), 2.60 – 2.68 (m, 1H), 1.96 – 2.07 (m, 1H), 1.43 – 1.46 (m, 9H), 1.23 – 1.36 (m, 1H), 0.63 – 0.66 (m, 2H), 0.33 – 0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 464.10 [M+Na] ⁺ .

Step 5: Synthesis of Compound (2S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

The compound ( 2S )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-di Carboxylic acid ester (252 mg, 0.57 mmol) was dissolved in dichloromethane (5 mL) solution, 4 mol/L HCl in ethyl acetate solution (5 mL) was added, stirred at room temperature for 30 min, and concentrated under reduced pressure to obtain colorless Liquid 202 mg, yield 94%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 6.92 (dd, J = 8.3, 1.6 Hz , 1H), 6.76 (t, J _FH = 75.5 Hz, 1H), 4.60 – 4.65 (m, 1H), 3.94 (d, J = 6.9 Hz, 2H), 3.90 (s, 3H), 3.78 – 3.83 (m , 1H), 3.63 – 3.73 (m, 1H), 3.33 – 3.40 (m, 1H), 2.82 – 2.89 (m, 1H), 2.20 – 2.29 (m, 1H), 1.27 – 1.35 (m, 1H), 0.63 – 0.68 (m, 2H), 0.37 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 342.40 [M+H-HCl] ⁺ .

Step 6: Compound ( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester Synthesis

Compound ( 2S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride (198 mg, 0.53 mmol) was dissolved in dichloromethane (10 mL), N,N -diisopropylethylamine (0.2 mL, 1.0 mmol) was added, acetonitrile chloride (70 mg, 0.8 mmol) was added dropwise in an ice bath, room temperature After stirring for 5.5 h, the reaction was stopped, water (10 mL) was added, and dichloromethane was extracted (10 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). : petroleum ether/ethyl acetate (v/v) = 2/1) to obtain a light brown liquid 176 mg, a yield of 87%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.12 (d, J = 8.6 Hz, 1H), 6.82 (s, 1H), 6.78-6.82 (m, 1H), 6.60 (t, J _FH = 75.5 Hz, 1H), 4.45 – 4.49 (m, 1H), 3.91 – 3.95 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.77 (s, 3H), 3.60 (t, J = 10.4 Hz, 1H), 3.36 – 3.45 (m, 1H), 2.62 – 2.68 (m, 1H), 2.11 (s, 3H), 2.02 – 2.09 (m, 1H), 1.27-1.33 (m, 1H), 0.63- 0.68 (m, 2H), 0.34-0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 384.15 [M+H] ⁺ .

Step 7: Synthesis of compound (2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid

The compound ( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester (92 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL), added lithium hydroxide monohydrate (51 mg, 1.22 mmol) and water (3 mL), reacted at 45 °C for 50 min, added dilute hydrochloric acid to adjust pH=1, and acetic acid Ethyl ester extraction (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 84 mg of a white solid with a yield of 94%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.09 – 7.13 (m, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.88 – 6.93 (m, 1H), 6.74 (t, J _FH = 74.9 Hz, 1H), 4.43 – 4.47 (m, 1H), 4.08 – 4.12 (m, 1H), 3.94 (d, J = 6.8 Hz, 2H), 3.58 – 3.64 (m, 1H), 3.50 – 3.57 (m, 1H), 2.72 – 2.78 (m, 1H), 2.14 (s, 3H), 2.00 – 2.05 (m, 1H), 1.27-1.36 (m, 1H), 0.63-0.67 (m, 2H), 0.37-0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 370.10 [M+H] ⁺ .

Step 8: Compound ( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (2,4-di Synthesis of Fluorobenzyl)pyrrolidine-2-carboxamide

The compound ( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (107 mg, 0.29 mmol), 2,4-difluorobenzylamine (48 mg, 0.34 mmol) and N -hydroxy-7-azabenzotriazole (59 mg, 0.43 mmol) were dissolved in dichloromethane (5 mL) , cooled to 0°C, added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (254 mg, 1.33 mmol) and N,N -diisopropylethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 4 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography ( Eluent: EA (v) = 100%) to give a white solid 101 mg in 70% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.34 – 7.40 (m, 1H), 7.22 (br.s, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 1.6 Hz, 1H), 6.83 – 6.89 (m, 2H), 6.63 (t, J _FH = 75.6 Hz, 1H), 4.55 – 4.59 (m, 1H), 4.44 – 4.52 (m, 2H), 3.90 – 3.96 (m, 1H), 3.89 (d, J = 6.9 Hz, 2H), 3.48 – 3.54 (m, 1H), 3.27 – 3.36 (m, 1H), 2.47 – 2.62 (m, 2H), 2.14 (s, 3H) ), 1.28-1.37 (m, 1H), 0.65-0.69 (m, 2H), 0.36-0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 495.20 [M+H] ⁺ .

Example 3: Compound (2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) - N - (pyridin-2 ylmethyl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (123 mg, 0.33 mmol), 2-pyridylmethylamine (96 mg, 0.89 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.83 mmol) and N- Hydroxy-7-azabenzotriazole (82 mg, 0.60 mmol) was dissolved in dichloromethane (6 mL), to this solution was added dropwise N , N -diisopropylethylamine ( 0.4 mL, 2.0 mmol), stirred at room temperature for 20 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1), 53 mg of pale yellow liquid was obtained, and the yield was 34%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.47 (d, J = 4.6 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H) ), 7.30-7.33 (m, 1H), 7.09-7.10 (m, 2H), 6.93-6.94 (m, 1H), 6.75 (t, J _FH = 75.8 Hz, 1H), 4.45-4.55 (m, 3H) , 4.09-4.13 (m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.63-3.69 (m, 1H), 3.48-3.56 (m, 1H), 2.66-2.73 (m, 1H), 2.16 (s, 3H), 2.05-2.12 (m, 1H), 1.28-1.34 (m, 1H), 0.62-0.67 (m, 2H), 0.37-0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 460.30 [M+H] ⁺ .

Example 4: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((5-fluoro Pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (121 mg, 0.33 mmol), (5-fluoropyridin-2-yl)methanamine (91 mg, 0.72 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (143 mg , 0.75 mmol) and N -hydroxy-7-azabenzotriazole (81 mg, 0.60 mmol) were dissolved in dichloromethane (6 mL), to this solution was added dropwise N , N - Diisopropylethylamine (0.4 mL, 2.0 mmol) was stirred at room temperature for 18 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 61 mg of a colorless liquid with a yield of 39%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.38 (s, 1H), 7.59-7.62 (m, 2H), 7.09-7.12 (m, 2H), 6.93-6.94 (m, 1H), 6.75 (t, J _FH = 75.4 Hz, 1H), 4.60 (s, 2H), 4.48-4.55 (m, 1H), 4.08-4.13 (m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.63-3.68 (m, 1H), 3.47-3.56 (m, 1H), 2.65-2.72 (m, 1H), 2.16 (s, 3H), 1.98-2.11 (m, 1H), 1.27-1.33 (m, 1H) ), 0.62-0.65 (m, 2H), 0.37-0.40 (m, 2H);

MS (ESI, pos.ion) m/z: 478.30 [M+H] ⁺ .

Example 5: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carbamoylamino ) methyl) ethyl picolinate

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

The compound (R) -1- tert-butyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H -pyrrole-1,2( 2H , 5H )-dicarboxylate (2.1 g, 5.9 mmol), 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene (861 -1-2) (5.8 g, 2.2 mmol), potassium phosphate (5.0 g, 24.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (88 mg, 0.12 mmol) in dry 1,4-dioxane (20 mL) solution, react at 100 °C for 5 h under nitrogen protection, filter the reaction solution with suction, add 20 mL of water to the filtrate, wash with ethyl acetate (15 mL) × 3) Extraction, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, concentrated, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1) to obtain a yellow-brown liquid 2.1 g, 74% yield.

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, pos.ion) m/z: 498.20 [M+Na] ⁺ .

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

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

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

MS (ESI, pos.ion) m/z: 376.05 [M+H-HCl] ⁺ .

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

The compound ( R )-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2-carboxylate methyl ester hydrochloride The salt (2.0 g, 4.9 mmol) was dissolved in dichloromethane (10 mL), N , N -diisopropylethylamine (4.0 mL, 24 mmol) was added, and acetyl chloride (1.1 g) was added after cooling to 0 °C , 14 mmol), stirred at room temperature for 3 h, then stopped the reaction, added water (20 mL × 3), stirred, extracted with dichloromethane (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) to obtain 1.8 g of a pale yellow liquid with a yield of 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, pos.ion) m/z: 418.60 [M+H] ⁺ .

Step 4: Synthesis of compound (2R )-1-acetoxy-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylate methyl ester

The compound ( R )-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2- Methyl carboxylate (4.5 g, 11 mmol) was dissolved in methanol (30 mL), Pd/C (450 mg, 10%) was added, hydrogen was passed through, the reaction was carried out at room temperature for 5 h, the catalyst was removed by filtration, and the filtrate was concentrated to obtain light brown Liquid 3.1 g, yield 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, pos.ion) m/z: 330.00 [M+H] ⁺ .

Step 5: Synthesis of compound (2R )-1-acetoxy-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylate 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 N , N -dimethylformamide (10 mL), potassium carbonate (1.8 g, 13 mmol) and 2-iodopropane (1.5 g, 8.8 mmol) were added, the reaction was heated at 80 °C for 4 h, and the solvent was removed under reduced pressure , the residue was added with water (50 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v /v ) = 50/1) to obtain 1.5 g of a 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, pos.ion) m/z: 372.30 [M+H] ⁺ .

Step 6: Synthesis of compound (2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylate methyl ester (750 mg, 2.02 mmol ) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL), lithium hydroxide monohydrate (297 mg, 7.08 mmol) was added, the reaction was stopped after 1 h at 50 °C, and diluted hydrochloric acid was added to adjust the pH of the solution to 1. The tetrahydrofuran was removed under reduced pressure, the residue was extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 665 mg of light brown liquid with a yield of 92%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.12 (d, J = 8.2 Hz, 1H), 7.04 – 7.08 (m, 1H), 6.93 (dd, J = 8.3, 1.8 Hz, 1H) , 6.69 (t, J _FH = 75.6 Hz, 1H), 4.63 – 4.71 (m, 1H), 4.44 – 4.48 (m, 1H), 4.09 – 4.13 (m, 1H), 3.57 – 3.63 (m, 1H), 3.50 – 3.56 (m, 1H), 2.72 – 2.79 (m, 1H), 2.14 (s, 3H), 1.99 – 2.08 (m, 1H), 1.35 (d, J = 6.0 Hz, 6H).

MS (ESI, pos.ion) m/z: 358.30 [M+H] ⁺ .

Step 7: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carbamoylamino) Synthesis of ethyl methyl)picolinate

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid (110 mg, 0.31 mmol), 6-Aminomethylpyridine-2-carboxylate ethyl ester hydrochloride (132 mg, 0.52 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (295 mg , 1.54 mmol) and N -hydroxy-7-azabenzotriazole (83 mg, 0.61 mmol) were dissolved in dichloromethane (10 mL), cooled to 0 °C, and N , N -diisopropyl was added Ethylamine (358 mg, 2.77 mmol) was reacted at room temperature for 6 h, washed with water (10 mL × 3), stirred, the organic phase was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v) = 50/1) to give a pale yellow solid 107 mg with a yield of 66%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.02 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H) , 7.48 (br.s, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.93 (s, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.55 (t, J _FH = 75.6 Hz , 1H), 4.66 – 4.78 (m, 2H), 4.53 – 4.64 (m, 2H), 4.12 (q, J = 7.0 Hz, 2H), 3.96 – 4.01 (m, 1H), 3.61 (t, J = 10.7 Hz, 1H), 3.30 – 3.42 (m, 1H), 2.59 – 2.66 (m, 1H), 2.40 – 2.49 (m, 1H), 2.17 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H) , 1.37 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 520.10 [M+H] ⁺ .

Example 6: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carbamoylamino ) methyl) pyridine carboxylic acid hydrochloride

The compound 6-((( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carbamoylamino)methyl ) ethyl pyridinecarboxylate (55 mg, 0.11 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (3 mL), lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added, and the reaction was carried out at 50 °C for 1.5 h After stopping, dilute hydrochloric acid was added to adjust the pH of the solution to 1, the solvent was removed under reduced pressure, the residue was extracted with ethyl acetate (10 mL × 2), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 55 mg of pale yellow solids, yield 98%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.06 (d, J = 7.0 Hz, 1H), 7.99 (t, J = 7.5 Hz, 1H), 7.76 (d, J = 7.4 Hz, 1H) ), 7.06 – 7.15 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.70 (t, J _FH = 75.6 Hz, 1H), 4.64 – 4.74 (m, 2H), 4.51 – 4.58 (m , 2H), 4.10 – 4.14 (m, 1H), 3.66 (t, J = 10.4 Hz, 1H), 3.47 – 3.56 (m, 1H), 2.67 – 2.75 (m, 1H), 2.16 (s, 3H), 2.04 – 2.13 (m, 1H), 1.35 (d, J = 5.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 492.10 [M+H-HCl] ⁺ .

Example 7: Compound 3-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carbamoylamino ) methyl) methyl benzoate

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid (110 mg, 0.31 mmol), Methyl 3-aminomethylbenzoate (86 mg, 0.52 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (297 mg, 1.55 mmol) and N- Hydroxy-7-azabenzotriazole (81 mg, 0.60 mmol) was dissolved in dichloromethane (10 mL), and after cooling to 0 °C, N , N -diisopropylethylamine (278 mg, 2.15 mmol), react at room temperature for 3 h, add water and wash (10 mL × 3), stir, separate the organic phase, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and conduct silica gel column chromatography (eluent: dichloromethane). /methanol (v/v) = 50/1) to obtain 112 mg of a colorless liquid with a yield of 72%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.95 – 7.96 (m, 2H), 7.53 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.13 ( d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 6.88 (dd, J = 8.2, 1.7 Hz, 1H), 6.57 (t, J _FH = 75.6 Hz, 1H), 4.57 – 4.68 (m, 2H), 4.49 – 4.58 (m, 2H), 3.94 – 3.99 (m, 1H), 3.92 (s, 3H), 3.52 (t, J = 10.8 Hz, 1H), 3.29 – 3.35 (m, 1H), 2.63 – 2.71 (m, 1H), 2.50 – 2.57 (m, 1H), 2.17 (s, 3H), 1.36 – 1.38 (m, 6H).

MS (ESI, pos.ion) m/z: 505.10 [M+H] ⁺ .

Example 8: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carbamoylamino )methyl)benzoic acid

The compound 6-((( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carbamoylamino)methyl ) methyl benzoate (63 mg, 0.12 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (3 mL), then lithium hydroxide monohydrate (26 mg, 0.62 mmol) was added, and the reaction was carried out at 50 °C for 1.5 h After stopping, dilute hydrochloric acid was added to adjust the pH of the solution to 1, the tetrahydrofuran was removed under reduced pressure, the residue was extracted with ethyl acetate (10 mL × 2), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 53 mg of white solid with a yield of 86 mg %.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.99 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.46 (d , J = 7.6 Hz, 1H), 7.06 – 7.12 (m, 2H), 6.93 (d, J = 8.5 Hz, 1H), 6.69 (t, J _FH = 75.6 Hz, 1H), 4.63 – 4.70 (m, 1H) ), 4.50 (s, 2H), 4.08 – 4.12 (m, 1H), 3.52 (t, J = 10.5 Hz, 1H), 3.44 – 3.55 (m, 1H), 3.31 – 3.38 (m, 1H), 2.64 – 2.72 (m, 1H), 2.15 (s, 3H), 2.01 – 2.12 (m, 1H), 1.35 (d, J = 5.8 Hz, 6H).

MS (ESI, pos.ion) m/z: 491.40 [M+H] ⁺ .

Example 9: Compound (2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) - N - (3- (hydroxymethyl) benzene yl)pyrrolidine-2-carboxamide

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid (60 mg, 0.17 mmol), 3-Aminobenzyl alcohol (62 mg, 0.50 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg, 0.85 mmol) and N -hydroxy-7- Azabenzotriazole (46 mg, 0.34 mmol) was dissolved in dichloromethane (10 mL), and after cooling to 0 °C, N , N -diisopropylethylamine (153 mg, 1.18 mmol) was added, The reaction was carried out at room temperature for 12 h, washed with water (10 mL), extracted with dichloromethane (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: Dichloromethane/methanol (v/v) = 35/1), 53 mg of light brown solid was obtained in 68% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.68 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.12 – 7.15 (m, 2H), 6.96 (s, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.56 (t, J _FH = 75.5 Hz, 1H), 4.74 – 4.78 (m, 1H), 4.52 – 4.64 (m, 3H), 3.97 – 4.01 (m, 1H), 3.62 – 3.67 (m, 1H), 3.34 – 3.45 (m, 1H), 2.58 – 2.66 (m, 1H), 2.46 – 2.54 (m, 1H), 2.20 (s, 3H), 1.37 (t, J = 5.9 Hz, 6H).

MS (ESI, pos.ion) m/z: 463.30 [M+H] ⁺ .

Example 10: Compound (2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) - N - (2- ethoxy-benzyl) pyrrolidin Alkyl-2-carboxamide

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid (60 mg, 0.17 mmol), 2-Ethoxybenzylamine (52 mg, 0.34 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg, 0.85 mmol) and N -hydroxy- 7-Azabenzotriazole (46 mg, 0.34 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and N , N -diisopropylethylamine (153 mg, 1.18 mmol) was added. ), reacted at room temperature for 12 h, washed with water (10 mL), extracted with dichloromethane (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluting Reagent: dichloromethane/methanol (v/v) = 35/1) to obtain 79 mg of white viscous solid with a yield of 96%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.23 – 7.29 (m, 2H), 7.08 – 7.14 (m, 2H), 6.96 (s, 1H), 6.84 – 6.92 (m, 2H), 6.56 (t, J _FH = 75.6 Hz, 1H), 4.51 – 4.62 (m, 3H), 4.37 – 4.47 (m, 1H), 4.10 (q, J = 6.9 Hz, 2H), 3.92 – 3.96 (m, 1H) , 3.51 (t, J = 10.8 Hz, 1H), 3.23 – 3.32 (m, 1H), 2.47 – 2.63 (m, 2H), 2.14 (s, 3H), 1.47 (t, J = 6.9 Hz, 3H), 1.37 (d, J = 5.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 491.25 [M+H] ⁺ .

Example 11: Compound (2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) - N - (2- ethoxyethyl benzyl)pyrrolidine-2-carboxamide

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (50 mg, 0.14 mmol), (2-ethoxyphenyl)methylamine (41 mg, 0.27 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.69 mmol) and N -hydroxy-7-azabenzotriazole (37 mg, 0.27 mmol) were dissolved in dichloromethane (10 mL), cooled to 0 °C, and N , N -diisopropylethyl acetate was added. Amine (107 mg, 0.83 mmol) was reacted at room temperature for 11 h, dichloromethane (15 mL) was added, the organic phase was washed with water (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to Separation by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) gave 39 mg of a white viscous solid with a yield of 57%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.23 – 7.28 (m, 1H), 7.09 – 7.12 (m, 2H), 6.85 – 6.94 (m, 4H), 6.62 (t, J _FH = 75.5 Hz, 1H), 4.53 – 4.59 (m, 2H), 4.39 – 4.47 (m, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.84 – 3.95 (m, 3H), 3.51 (t, J = 10.7 Hz, 1H), 3.24 – 3.34 (m, 1H), 2.89 – 2.95 (m, 0.3H), 2.48 – 2.61 (m, 1.7H), 2.14 (s, 2.4H), 1.90 (s, 0.6H) , 1.45 (t, J = 7.0 Hz, 3H), 1.28 – 1.36 (m, 1H), 0.69 – 0.70 (m, 2H), 0.36 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 503.10 [M+H] ⁺ .

Example 12: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -formamido)methyl) -N,N -dimethylnicotinamide

Step 1: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of methyl formamido)methyl)nicotinate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (300 mg, 0.81 mmol), methyl 6-(aminomethyl)nicotinate (206 mg, 1.24 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (780 mg, 4.07 mmol) and N -hydroxy-7-azabenzotriazole (166 mg, 1.22 mmol) were dissolved in dichloromethane (5 mL), to this solution was added dropwise N , N -dichloromethane at 0°C Isopropylethylamine (0.6 mL, 4.0 mmol) was reacted at room temperature for 17 h, washed with water (15 mL), and then extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the solution was concentrated. The liquid was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 213 mg of a light yellow viscous solid with a yield of 51%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.15 (s, 1H), 8.28 (dd, J = 8.1, 2.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.12 ( d, J = 8.2 Hz, 1H), 6.91 (s, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.62 (t, J _FH = 75.6 Hz, 1H), 4.61 – 4.69 (m, 3H) , 3.94 – 3.99 (m, 1H), 3.97 (s, 3H), 3.88 (d, J = 6.9 Hz, 2H), 3.57 (t, J = 10.7 Hz, 1H), 3.31 – 3.41 (m, 1H), 2.46 – 2.63 (m, 2H), 2.16 (s, 3H), 1.27 – 1.35 (m, 1H), 0.65 – 0.69 (m, 2H), 0.36 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 518.10 [M+H] ⁺ .

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

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)methyl nicotinate (154 mg, 0.3 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL), and then lithium hydroxide monohydrate (86 mg, 2.05 mmol) was added, 50 The reaction was stopped after 3 h at ℃, diluted hydrochloric acid was added to adjust the pH of the solution to 1, and then extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 137 mg of white solid with a yield of 91%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 9.07 (s, 1H), 8.42 (dd, J = 8.2, 1.9 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.93 – 6.96 (m, 1H), 6.75 (t, J _FH = 75.7 Hz, 1H), 4.51 – 4.73 (m, 2H), 4.10 – 4.14 (m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.66 (t, J = 10.6 Hz, 1H), 3.51 – 3.56 (m, 1H), 2.68 – 2.74 (m, 1H), 2.17 (s, 3H), 2.01 – 2.13 (m, 2H), 1.27 – 1.35 (m, 1H), 0.62 – 0.67 (m, 2H), 0.37 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 504.10 [M+H] ⁺ .

Step 3: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of formamido)methyl) -N,N -dimethylnicotinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)nicotinic acid (130 mg, 0.26 mmol), dimethylamine hydrochloride (103 mg, 1.26 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide The acid salt (249 mg, 1.3 mmol) and N -hydroxy-7-azabenzotriazole (58 mg, 0.43 mmol) were dissolved in dichloromethane (5 mL), and the solution was added dropwise at 0°C N , N -diisopropylethylamine (0.28 mL, 1.7 mmol) was added, the reaction was carried out at room temperature for 19 h, washed with water (15 mL), and then extracted with dichloromethane (10 mL × 3). The organic phase was washed with anhydrous sodium sulfate. After drying, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 103 mg of white solid with a yield of 75%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.60 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.61 (br.s, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.62 (t, J _FH = 75.6 Hz, 1H), 4.49 -4.68 (m, 3H), 3.91-3.98 (m, 1H), 3.88 (d, J = 6.8 Hz, 2H), 3.54-3.60 (m, 1H), 3.26-3.41 (m, 1H), 3.13 (s , 3H), 3.01 (s, 3H), 2.41-2.62 (m, 2H), 2.14 (s, 3H), 1.24-1.35 (m, 1H), 0.62-0.67 (m, 2H), 0.34-0.39 (m , 2H).

MS (ESI, pos.ion) m/z: 531.15 [M+H] ⁺ .

Example 13: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((4-( 1-Hydroxyethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (748-1 ) (92 mg, 0.25 mmol), compound 1-(2-(aminomethyl)pyridin-4-yl)ethanol (101 mg, 0.54 mmol), 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (143 mg, 0.75 mmol) and N -hydroxy-7-azabenzotriazole (72 mg, 0.53 mmol) were dissolved in dichloromethane (6 mL) at room temperature To this solution was added dropwise N , N -diisopropylethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 17 h, added water (50 mL), extracted with dichloromethane (5 mL × 3), the organic phase was It was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 52 mg of white solid, with a yield of 41%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.81-8.84 (m, 0.3H), 8.53-8.58 (m, 0.7H), 8.39-8.41 (m, 1H), 7.36 (s, 0.7H), 7.28 (s, 0.3H), 7.22 (s, 1H), 7.10-7.14 (m, 1H), 7.05-7.06 (m, 1H), 7.03 (t, J _FH = 78.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 5.33-5.39 (m, 1H), 4.64-4.73 (m, 1H), 4.35-4.42 (m, 3H), 4.19-4.23 (m, 0.3H), 4.05 -4.09 (m, 0.7H), 3.90 (d, J = 6.9 Hz, 2H), 3.34-3.47 (m, 2H), 2.51-2.64 (m, 1H), 2.02 (s, 3H), 1.89-1.98 ( m, 1H), 1.31 (d, J = 6.5 Hz, 3H), 1.24-1.27 (m, 1H), 0.54-0.60 (m, 2H), 0.31-0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 504.20 [M+H] ⁺ .

Example 14: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( 1-Hydroxyethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (82 mg, 0.22 mmol), compound 1-(6-(aminomethyl)pyridin-2-yl)ethanol (73 mg, 0.48 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide The hydrochloride salt (123 mg, 0.64 mmol) and N -hydroxy-7-azabenzotriazole (74 mg, 0.54 mmol) were dissolved in dichloromethane (6 mL) and added dropwise to this solution at room temperature N , N -diisopropylethylamine (0.4 mL, 2.0 mmol) was added, stirred at room temperature for 17 h, washed with water (50 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sodium sulfate After drying, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 43 mg of a white solid with a yield of 38%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.75-8.83 (m, 0.2H), 8.50-8.62 (m, 0.8H), 7.70-7.79 (m, 1H), 7.32-7.39 ( m, 1H), 7.24-7.26 (m, 1H), 7.06-7.14 (m, 2H), 7.03 (t, J _FH = 74.6 Hz, 1H), 6.86-6.90 (m, 1H), 5.26-5.43 (m , 1H), 4.64-4.75 (m, 1H), 4.28-4.44 (m, 3H), 4.02-4.12 (m, 1H), 3.90 (d, J = 6.1 Hz, 2H), 3.43-3.57 (m, 2H) ), 2.56-2.67 (m, 1H), 2.03 (s, 3H), 1.86-1.98 (m, 1H), 1.30-1.36 (m, 3H), 1.23-1.26 (m, 1H), 0.51-0.62 (m , 2H), 0.28-0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 504.20 [M+H] ⁺ .

Example 15: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( Hydroxymethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (85 mg, 0.23 mmol), compound (6-(aminomethyl)pyridin-2-yl)methanol (61 mg, 0.35mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide salt The acid salt (143 mg, 0.75 mmol) and N -hydroxy-7-azabenzotriazole (72 mg, 0.53 mmol) were dissolved in dichloromethane (6 mL), and to this solution was added dropwise at room temperature N , N -diisopropylethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 20 h, washed with water (50 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was dried over anhydrous sodium sulfate , the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 64 mg of white solid with a yield of 56%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.52-8.55 (m, 1H), 7.71-7.75 (m, 1H), 7.25-7.35 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H), 7.06 (s, 1H), 7.03 (t, J _FH = 74.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.36-5.41 (m, 1H), 4.52 (d , J = 4.8 Hz, 2H), 4.27-4.42 (m, 3H), 4.05-4.09 (m, 1H), 3.90 (d, J = 6.5 Hz, 2H), 3.40-3.51 (m, 2H), 2.55- 2.64 (m, 1H), 2.03 (s, 3H), 1.88-1.98 (m, 1H), 1.23-1.35 (m, 1H), 0.53-0.59 (m, 2H), 0.31-0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 490.20 [M+H] ⁺ .

Example 16: Compound (3-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 2-Methylamino)methyl)phenyl)carbamate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (748-1 ) (85 mg, 0.23 mmol), compound (3-(aminomethyl)phenyl)carbamate methyl ester hydrochloride (803-2) (96 mg, 0.53 mmol), 1-ethyl-(3-di Methylaminopropyl)carbodiimide hydrochloride (148 mg, 0.77 mmol) and N -hydroxy-7-azabenzotriazole (74 mg, 0.54 mmol) were dissolved in dichloromethane (6 mL) ), N , N -diisopropylethylamine (0.4 mL, 2.0 mmol) was added dropwise to this solution at room temperature, stirred at room temperature for 14 h, added water (50 mL), and extracted with dichloromethane (5 mL). × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 46 mg of white solid, which was collected rate 38%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.60-9.64 (m, 1H), 8.72-8.75 (m, 0.3H), 8.41-8.43 (m, 0.7H), 7.37-7.42 ( m, 1H), 7.28-7.32 (m, 1H), 7.20-7.23 (m, 1H), 7.09-7.13 (m, 1H), 7.04-7.05 (m, 1H), 7.02 (t, J _FH = 69.5 Hz , 1H), 6.88-6.94 (m, 2H), 4.18-4.34 (m, 3H), 4.03-4.07 (m, 1H), 3.89 (d, J = 6.8 Hz, 2H), 3.63 (s, 3H), 3.39-3.49 (m, 2H), 2.56-2.61 (m, 1H), 2.01 (s, 3H), 1.87-1.96 (m, 1H), 1.22-1.33 (m, 1H), 0.54-0.60 (m, 2H) ), 0.31-0.35 (m, 2H).

MS (ESI, pos.ion) m/z: 532.20 [M+H] ⁺ .

Example 17: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((pyrimidine-2 -yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (92 mg, 0.25 mmol), compound pyrimidine-2-methylamine (103 mg, 0.71 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (150 mg, 0.78 mmol) and N -Hydroxy-7-azabenzotriazole (71 mg, 0.52 mmol) was dissolved in dichloromethane (6 mL), and N , N -diisopropylethylamine (0.4 mL, 2.0 mL) was added at room temperature mmol), stirred at room temperature for 15 h, washed with water (50 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (elution Reagent: dichloromethane/methanol (v/v) = 15/1) to obtain 49 mg of white solid with a yield of 42%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.75 (d, J = 4.7 Hz, 2H), 7.39 (t, J = 4.4 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.06 (s, 1H), 7.03 (t, J _FH = 74.9 Hz, 1H), 6.86-6.90 (m, 1H), 4.38-4.56 (m, 3H), 4.19-4.24 (m, 0.5H) , 4.03-4.07 (m, 0.5H), 3.87-3.90 (m, 2H), 3.39-3.48 (m, 2H), 2.74-2.80 (m, 0.5H), 2.74-2.80 (m, 0.5H), 1.98 -2.07 (m, 1H), 2.01 (s, 3H), 1.23-1.32 (m, 1H), 0.53-0.61 (m, 2H), 0.29-0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 461.25 [M+H] ⁺ .

Example 18: Compound ( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( 1-Hydroxyethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

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

The compound ( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester (410 mg, 1.07 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide monohydrate (230 mg, 5.48 mmol) was added, and the reaction was stopped after 4 h at 50 °C. The solvent was removed, diluted hydrochloric acid was added to adjust the pH of the solution to 1, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 365 mg of white solid with a yield of 92%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.13 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6.80-6.81 (m, 1H), 6.61 (t, J _FH = 75.5 Hz, 1H), 4.56-4.60 (m, 1H), 3.94-3.98 (m, 1H), 3.87 (d, J = 6.9 Hz, 2H), 3.51-3.57 (m, 1H), 3.34-3.43 (m , 1H), 2.62 – 2.69 (m, 1H), 2.33-2.41 (m, 1H), 2.18 (s, 3H), 1.25 – 1.34 (m, 1H), 0.63-0.68 (m, 2H), 0.34-0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 370.20 [M+H] ⁺ .

Step 2: ( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-(1- Synthesis of Hydroxyethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (97 mg, 0.26 mmol), 1-(6-(aminomethyl)pyridin-2-yl)ethanol dihydrochloride (84 mg, 0.55 mmol), 1-ethyl-(3-dimethylaminopropyl)carboline Diimine hydrochloride (103 mg, 0.54 mmol) and N -hydroxy-7-azabenzotriazole (69 mg, 0.51 mmol) were dissolved in dichloromethane (4 mL), cooled to 0 °C, N , N -diisopropylethylamine (0.22 mL, 1.3 mmol) was added, stirred at room temperature for 7 h, the reaction solution was washed with water (5 mL × 3), dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography Separation (eluent: dichloromethane/methanol (v/v) = 20/1) gave a pale yellow solid 68 mg, yield 51%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.55 (t, J = 5.9 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.34-7.40 (m, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.10-7.14 (m, 1H), 7.05-7.07 (m, 1H), 7.03 (t, J _FH = 74.9 Hz, 1H), 6.89 (d, J = 9.5 Hz, 1H), 5.33-5.35 (m, 1H), 4.64-4.72 (m, 1H), 4.32-4.41 (m, 3H), 4.06-4.10 (m, 1H), 3.90 (d, J = 6.9 Hz, 2H), 3.37-3.52 (m, 2H), 2.58-2.65 (m, 1H), 2.03 (s, 3H), 1.84-1.93 (m, 1H), 1.33-1.36 (m, 3H), 1.24-1.27 ( m, 1H), 0.55-0.60 (m, 2H), 0.31-0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 504.30 [M+H] ⁺ .

Example 19: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((4-( Hydroxymethyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound 2-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)isonicotinic acid methyl ester (79 mg, 0.15 mmol) was dissolved in tetrahydrofuran (6 mL), lithium borohydride (48 mg, 2.20 mmol) was added in an ice bath, and the reaction was stopped after 4 h at room temperature. Water (50 mL) was added, extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/ v) = 20/1) to obtain 36 mg of white solid, yield 48%.

MS (ESI, pos.ion) m/z: 490.20 [M+H] ⁺ .

Example 20: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((4-( 2-Hydroxypropyl-2-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (203 mg, 0.55 mmol), 2-(2-(aminomethyl)pyridin-4-yl)isopropanol dihydrochloride (186 mg, 1.12 mmol), 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (223 mg, 1.16 mmol) and N -hydroxy-7-azabenzotriazole (115 mg, 0.85 mmol) were dissolved in dichloromethane (6 mL) and cooled to 0 ℃, add N , N -diisopropylethylamine (0.5 mL, 3.0 mmol), stir at room temperature for 21 h, add water (15 mL), extract with dichloromethane (5 mL × 3), combine the organic phases, It was dried with anhydrous sodium sulfate, the solvent was removed, and the residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) to obtain 221 mg of white solid with a yield of 77%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.41 (d, J = 5.2 Hz, 1H), 7.64 (s, 1H), 7.43 (d, J = 3.9 Hz, 1H), 7.08-7.12 (m, 2H), 6.90-6.94 (m, 1H), 6.75 (t, J _FH = 75.7 Hz, 1H), 4.50-4.65(m, 1H), 4.50-4.60(m, 2H), 4.09-4.13 ( m, 1H), 3.93 (d, J = 6.8 Hz, 2H), 3.65 (d, J = 10.6 Hz, 1H), 3.47-3.55 (m, 1H), 2.67-2.74 (m, 1H), 2.15 (s , 3H), 2.08-2.15 (m, 1H), 1.54 (d, J = 3.4 Hz, 6H), 1.27-1.34 (m, 1H), 0.62-0.67 (m, 2H), 0.36-0.41 (m, 2H) ).

MS (ESI, pos.ion) m/z: 518.20 [M+H] ⁺ .

Example 21: ( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((4-(2 -Hydroxypropan-2-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100 mg, 0.27 mmol), 2-(2-(aminomethyl)pyridin-4-yl)isopropanol dihydrochloride (77 mg, 0.33 mmol), 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (408 mg, 2.13 mmol) and N -hydroxy-7-azabenzotriazole (87 mg, 0.64 mmol) were dissolved in dichloromethane (5 mL) at 0°C Under cooling, N , N -diisopropylethylamine (0.45 mL, 2.6 mmol) was added dropwise, stirred at room temperature for 12 h, added water (20 mL), extracted with dichloromethane (10 mL × 3), the organic phase was It was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 91 mg of white solid with a yield of 64%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.45 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 7.19 (d, J = 4.4 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.63 (t, J _FH = 75.6 Hz, 1H), 4.78 – 4.84 (m, 1H), 4.51 – 4.55 (m, 1H), 4.41 – 4.46 (m, 1H), 3.93 – 3.97 (m, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.60 – 3.65 (m, 1H), 3.32 – 3.43 (m, 1H), 2.57 – 2.64 (m, 1H), 2.37 – 2.45 (m, 1H), 2.14 (s, 3H), 1.55 (s, 3H), 1.57 (s, 3H), 1.25-1.37 (m , 1H), 0.65-0.69 (m, 2H), 0.36-0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 518.15 [M+H] ⁺ .

Example 22: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( 2-Hydroxypropyl-2-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (67 mg, 0.18 mmol), 2-(6-(aminomethyl)pyridin-2-yl)propane-2-hydroxy (93 mg, 0.56 mmol), 1-ethyl-(3-dimethylaminopropyl)carboline Diimine hydrochloride (103 mg, 0.54 mmol) and N -hydroxy-7-azabenzotriazole (65 mg, 0.48 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C, Add N , N -diisopropylethylamine (0.3 mL, 2.0 mmol), stir at room temperature for 18 h, add water (15 mL), extract with dichloromethane (5 mL × 3), and dry the organic phase with anhydrous sodium sulfate , the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 32 mg of white solid with a yield of 34%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.76 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H) ), 7.09-7.12 (m, 2H), 6.92-6.94 (m, 1H), 6.74 (t, J _FH = 75.7 Hz, 1H), 4.50-4.60 (m, 3H), 4.09-4.13 (m, 1H) , 3.93 (d, J = 6.9 Hz, 2H), 3.63-3.68 (m, 1H), 3.48-3.55 (m, 1H), 2.66-2.73 (m, 1H), 2.16 (s, 3H), 2.03-2.12 (m, 1H), 1.54 (s, 6H), 1.27-1.35 (m, 1H), 0.62-0.67 (m, 2H), 0.37-0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 518.20 [M+H] ⁺ .

Example 23: ( 2R )-4-(3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((4-(2-hydroxypropane-2- yl)pyridin-2-yl)methyl)-1-(methylsulfonyl)pyrrolidine-2-carbamide

Step 1: Compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxy Synthesis of Methyl Acid

Compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride (418 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL), N , N -diisopropylethylamine (0.36 mL, 2.2 mmol) and methanesulfonyl chloride (0.13 mL, 1.7 mmol) were added at 0°C, and the mixture was heated to room temperature. The reaction was stopped after stirring for 4 h, water (15 mL) was added, and dichloromethane was extracted (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (eluent: EtOAc (v) = 100 %) to obtain 154 mg of white solid with a yield of 33%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.11 (d, J = 7.9 Hz, 1H), 6.77-6.79 (m, 2H), 6.59 (t, J _FH = 71.0 Hz, 1H), 4.63 – 4.67 (m, 1H), 4.05 – 4.08 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.78 (s, 3H), 3.38 – 3.46 (m, 1H), 3.30 – 3.37 (m , 1H), 3.08 (s, 3H), 2.74 – 2.81 (m, 1H), 2.04 – 2.13 (m, 1H), 1.24 – 1.33 (m, 1H), 0.63 – 0.68 (m, 2H), 0.34 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 420.20 [M+H] ⁺ .

Step 2: Compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxy acid synthesis

The compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxylate methyl The ester (151 mg, 0.36 mmol) was dissolved in tetrahydrofuran (5 mL), lithium hydroxide monohydrate (75 mg, 1.79 mmol) and water (5 mL) were added, and the reaction was carried out at 45 °C for 1 h, and dilute hydrochloric acid was added to adjust pH=1 , extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 143 mg of white solid with a yield of 98%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.10 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 6.90 (dd, J = 8.2, 1.8 Hz , 1H), 6.73 (t, J _FH = 74.9 Hz, 1H), 4.49 – 4.53 (m, 1H), 3.96 – 4.00 (m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.41 – 3.50 (m, 2H), 3.08 (s, 3H), 2.80 – 2.84 (m, 1H), 2.09 – 2.17 (m, 1H), 1.28-1.36 (m, 1H), 0.62-0.67 (m, 2H), 0.37 -0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 406.20 [M+H] ⁺ .

Step 3: Compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((4-(2-hydroxypropane-2- Synthesis of yl)pyridin-2-yl)methyl)-1-(methylsulfonyl)pyrrolidine-2-carboxamide

The compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methylsulfonyl)pyrrolidine-2-carboxylic acid ( 66 mg, 0.16 mmol), 2-(2-(aminomethyl)pyridin-4-yl)isopropanol dihydrochloride (58 mg, 0.24 mmol), 1-ethyl-(3-dimethylamino) propyl)carbodiimide hydrochloride (156 mg, 0.81 mmol) and N -hydroxy-7-azabenzotriazole (33 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL), N , N -diisopropylethylamine (0.2 mL, 1.0 mmol) was added dropwise to this solution at 0°C, stirred at room temperature for 5 h, added with water (15 mL), and extracted with dichloromethane (5 mL × 3 ), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 87 mg of a pale yellow solid, which was collected rate of 96%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.44 (d, J = 5.2 Hz, 1H), 7.54 (br.s, 1H), 7.43 (s, 1H), 7.25 (d, J = 5.9 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.79 (d, J = 10.3 Hz, 1H), 6.59 (t, J _FH = 75.6 Hz, 1H), 4.47 – 4.65 (m, 3H), 3.99 – 4.03 (m, 1H), 3.85 (d, J = 6.8 Hz, 2H), 3.33 – 3.47 (m, 2H), 3.02 (s, 3H), 2.76 – 2.82 (m , 1H), 2.25 – 2.33 (m, 1H), 1.54 (s, 6H), 1.25-1.32 (m, 1H), 0.61-0.66 (m, 2H), 0.32-0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 554.30 [M+H] ⁺ .

Example 24: Compound ( 2R )-1-Acetyl- N- (2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-4-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamide

Step 1: Compound 2-(( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Synthesis of Acylamino)-2-(2,4-difluorophenyl)acetate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid) (178 mg , 0.48 mmol), 2-amino-2-(2,4-difluorophenyl)ethyl acetate hydrochloride (149 mg, 0.59 mmol) and N -hydroxy-7-azabenzotriazole (101 mg, 0.74 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (467 mg, 2.44 mmol) and N , N -diisopropylethylamine (0.5 mL, 3.0 mmol), reacted at room temperature for 16 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was washed with anhydrous After drying over sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/3) to obtain 147 mg of white solid, with a yield of 54%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.33-7.44 (m, 1H), 7.09-7.12 (m, 1H), 6.82-6.91 (m, 4H), 6.62 (t, J _FH = 75.6 Hz, 1H), 5.71 – 5.74 (m, 1H), 4.62 – 4.68 (m, 1H), 4.17 – 4.27 (m, 2H), 3.90 – 3.98 (m, 1H), 3.88 (d, J = 6.8 Hz, 2H), 3.44 – 3.52 (m, 1H), 3.28 – 3.38 (m, 1H), 2.46 – 2.57 (m, 2H), 2.10 – 2.19 (m, 3H), 1.27-1.35 (m, 1H), 1.20 – 1.23 (m, 3H), 0.64-0.69 (m, 2H), 0.37-0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 567.30 [M+H] ⁺ .

Step 2: Compound 2-(( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Synthesis of acylamino)-2-(2,4-difluorophenyl)acetic acid

The compound 2-(( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino )-2-(2,4-difluorophenyl)ethyl acetate (140 mg, 0.25 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL), and then lithium hydroxide monohydrate ( 54 mg, 1.29 mmol), the reaction was stopped after 3 h at 50 °C, concentrated hydrochloric acid was added to adjust the pH of the solution to 1, extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain a white solid 131 mg, the yield is 98%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.43 – 7.53 (m, 1H), 6.91 – 7.12 (m, 5H), 6.53 – 6.94 (m, 1H), 5.74 – 5.78 (m, 1H) ), 4.54 – 4.68 (m, 1H), 4.05 – 4.15 (m, 1H), 3.89 – 3.95 (m, 2H), 3.56 – 3.63 (m, 1H), 3.44 – 3.52 (m, 1H), 2.57 – 2.76 (m, 1H), 2.03 – 2.13 (m, 4H), 1.27-1.36 (m, 1H), 0.61-0.67 (m, 2H), 0.37-0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 539.20 [M+H] ⁺ .

Step 3: Compound ( 2R )-1-Acetyl- N- (2-amino-1-(2,4-difluorophenyl)-2-oxoethyl)-4-(3-(cyclo) Synthesis of propylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamide

The compound 2-(( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino )-2-(2,4-difluorophenyl)acetic acid (130 mg, 0.24 mmol), ammonium chloride (132 mg, 2.4 mmol), 1-ethyl-(3-dimethylaminopropyl)carbon Diimide hydrochloride (242 mg, 1.26 mmol) and N -hydroxy-7-azabenzotriazole (51 mg, 0.37 mmol) were dissolved in dichloromethane (5 mL) at 0°C N , N -diisopropylethylamine (0.4 mL, 2.0 mmol) was added dropwise to this solution, the reaction was carried out at room temperature for 16 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), the organic The phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/3) to obtain 37 mg of white solid, yield 29% .

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.41-7.50 (m, 1H), 7.05-7.14 (m, 2H), 6.96-7.05 (m, 2H), 6.88-6.95 (m, 1H) ), 6.73 (t, J _FH = 75.6 Hz, 1H), 5.72 (s, 1H), 4.44 – 4.52 (m, 1H), 4.03 – 4.12 (m, 1H), 3.92 (d, J = 5.9 Hz, 1H) ), 3.61 – 3.67 (m, 1H), 3.43 – 3.55 (m, 1H), 2.50 – 2.57 (m, 3H), 3.13 (m, 3H), 2.03 – 2.09 (m, 1H), 1.31-1.40 (m , 1H), 0.60-0.66 (m, 2H), 0.35-0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 538.15 [M+H] ⁺ .

Example 25: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N , N -lutidyl pyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (172 mg, 0.34 mmol), dimethylamine hydrochloride (142 mg, 1.74 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide The acid salt (321 mg, 1.67 mmol) and N -hydroxy-7-azabenzotriazole (72 mg, 0.53 mmol) were dissolved in dichloromethane (5 mL), and the solution was added dropwise at 0°C N , N -diisopropylethylamine (0.4 mL, 2.0 mmol) was added, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sodium sulfate After drying, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 94 mg of white solid, with a yield of 52%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.92 (t, J = 7.9 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H) ), 7.12 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.92 – 6.94 (m, 1H), 6.75 (t, J _FH = 75.7 Hz, 1H), 4.48 – 4.65 (m, 3H) ), 4.09 – 4.13 (m, 1H), 3.93 (d, J = 6.8 Hz, 2H), 3.66 (t, J = 10.6 Hz, 1H), 3.49 – 3.56 (m, 1H), 3.10 (s, 3H) , 3.01 (s, 3H), 2.66 – 2.73 (m, 1H), 2.19 (s, 3H), 2.06 – 2.16 (m, 1H), 1.27 – 1.33 (m, 1H), 0.62 – 0.67 (m, 2H) , 0.36 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 531.10 [M+H] ⁺ .

Example 26: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -formamido)methyl)picolinic acid

Step 1: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of ethyl formamido)methyl)picolinate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (201 mg, 0.54 mmol), 6-(aminomethyl)picolinate ethyl ester hydrochloride (142 mg, 0.66 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 516 mg, 2.69 mmol) and N -hydroxy-7-azabenzotriazole (111 mg, 0.82 mmol) were dissolved in dichloromethane (5 mL), and N was added dropwise to this solution at 0 °C, N -diisopropylethylamine (0.6 mL, 4.0 mmol) was reacted at room temperature for 16 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, removed The solvent and the concentrated solution were separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 216 mg of white viscous solid with a yield of 74%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.02 (d, J = 7.5 Hz, 1H), 7.83 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H) , 7.11 (d, J = 8.1 Hz, 1H), 6.89 (s, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.62 (t, J _FH = 75.7 Hz, 1H), 4.59 – 4.77 (m , 3H), 4.47 (q, J = 7.1 Hz, 2H), 3.95 – 4.00 (m, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.61 (t, J = 10.6 Hz, 1H), 3.32 – 3.39 (m, 1H), 2.58 – 2.65 (m, 1H), 2.40 – 2.48 (m, 1H), 2.17 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H), 1.27 – 1.33 (m , 1H), 0.64 – 0.69 (m, 2H), 0.35 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 532.30 [M+H] ⁺ .

Step 2: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of carboxylamino)methyl)picolinic acid

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)ethyl picolinate (232 mg, 0.44 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (4 mL), and lithium hydroxide monohydrate (72 mg, 1.72 mmol) was added, at 50°C The reaction was stopped after 3 h, hydrochloric acid was added to adjust the pH of the solution to 1, extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 213 mg of a white solid with a yield of 97%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.06 (d, J = 7.5 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H) ), 7.11 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.92 – 6.94 (m, 1H), 6.74 (t, J _FH = 75.7 Hz, 1H), 4.51 – 4.73 (m, 3H) ), 4.09 – 4.14 (m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.66 (t, J = 10.6 Hz, 1H), 3.49 – 3.55 (m, 1H), 2.67 – 2.73 (m, 1H), 2.16 (s, 3H), 2.07 – 2.12 (m, 1H), 1.27 – 1.35 (m, 1H), 0.62 – 0.67 (m, 2H), 0.37 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 504.30 [M+H] ⁺ .

Example 27: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl)pyridylamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (101 mg, 0.20 mmol), ammonium chloride (112 mg, 2.09 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 96 mg, 0.50 mmol) and N -hydroxy-7-azabenzotriazole (67 mg, 0.49 mmol) were dissolved in dichloromethane (6 mL), and N was added dropwise to this solution at 0°C, N -diisopropylethylamine (0.2 mL, 1.0 mmol), stirred at room temperature for 6 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed , the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 73 mg of white solid with a yield of 72%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.01 (d, J = 7.8 Hz, 1H), 7.95 (t, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H) ), 7.08-7.12 (m, 2H), 6.91-6.95 (m, 1H), 6.74 (t, J _FH = 75.7 Hz, 1H), 4.54-4.71 (m, 3H), 4.09-4.13 (m, 1H) , 3.93 (d, J = 6.9 Hz, 2H), 3.63-3.68 (m, 1H), 3.47-3.56 (m, 1H), 2.66-2.73 (m, 1H), 2.16 (s, 3H), 2.03-2.13 (m, 1H), 1.27-1.35 (m, 1H), 0.62-0.67 (m, 2H), 0.34-0.40 (m, 2H);

MS (ESI, pos.ion) m/z: 503.30 [M+H] ⁺ .

Example 28: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -picolinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (97 mg, 0.19 mmol), methylamine hydrochloride (81 mg, 1.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (86 mg, 0.45 mmol) and N -hydroxy-7-azabenzotriazole (56 mg, 0.41 mmol) were dissolved in dichloromethane (6 mL) and added dropwise to this solution at 0°C N , N -diisopropylethylamine (0.2 mL, 1.0 mmol), stirred at room temperature for 20 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, The solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 58 mg of a white solid with a yield of 58%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.91-7.98 (m, 2H), 7.60 (d, J = 7.3 Hz, 1H), 7.08-7.12 (m, 2H), 6.92-6.94 ( m, 1H), 6.74 (t, J _FH = 75.7 Hz, 1H), 4.51-4.61 (m, 3H), 4.07-4.17 (m, 1H), 3.92 (d, J = 6.6 Hz, 2H), 3.61- 3.72 (m, 1H), 3.46-3.57 (m, 1H), 2.97 (s, 3H), 2.65-2.76 (m, 1H), 2.16 (s, 3H), 2.06-2.14 (m, 1H), 1.27- 1.34 (m, 1H), 0.62-0.66 (m, 2H), 0.36-0.40 (m, 2H);

MS (ESI, pos.ion) m/z: 517.30 [M+H] ⁺ .

Example 29: Compound 2-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -formamido)methyl) -N , N -dimethylisonicotinamide

Step 1: Compound 2-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of methyl formamido)methyl)isonicotinate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (103 mg, 0.28 mmol), methyl 2-(aminomethyl)isonicotinate (102 mg, 0.61 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg , 0.59 mmol) and N -hydroxy-7-azabenzotriazole (65 mg, 0.48 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C, and N , N -diisopropyl was added Ethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 17 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v) = 15/1) gave 103 mg of pale yellow liquid with a yield of 71%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.67-8.70 (m, 1H), 7.96 (s, 1H), 7.80-7.81 (m, 1H), 7.09-7.12 (m, 2H), 6.93-6.95 (m, 1H), 6.74 (t, J _FH = 75.7 Hz, 1H), 4.52-4.66 (m, 3H), 4.09-4.14 (m, 1H), 3.93 (s, 3H), 3.93 (d , J = 4.6 Hz, 2H), 3.63-3.68 (m, 1H), 3.47-3.57 (m, 1H), 2.69-2.76 (m, 1H), 2.15 (s, 3H), 2.07-2.15 (m, 1H) ), 1.27-1.33 (m, 1H), 0.62-0.66 (m, 2H), 0.32-0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 518.30 [M+H] ⁺ .

Step 2: Compound 2-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of formamido)methyl)isonicotinic acid

The compound 2-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)isonicotinate (97 mg, 0.19 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (4 mL), lithium hydroxide monohydrate (43 mg, 1.03 mmol) was added, 50 The reaction was stopped after 2 h at ℃, hydrochloric acid was added to adjust the pH of the solution to 1, extracted with ethyl acetate (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 92 mg of a white solid with a yield of 97%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.66-8.69 (m, 1H), 7.96 (s, 1H), 7.82 (d, J = 4.8 Hz, 1H), 7.05-7.12 (m, 2H), 6.91-6.95 (m, 1H), 6.74 (t, J _FH = 75.7 Hz, 1H), 4.52-4.69 (m, 3H), 4.09-4.13 (m, 1H), 3.92 (d, J = 6.8 Hz, 2H), 3.61-3.67 (m, 1H), 3.47-3.56 (m, 1H), 2.69-2.75 (m, 1H), 2.13-2.23 (m, 1H), 2.15 (s, 3H), 1.24- 1.35 (m, 1H), 0.61-0.66 (m, 2H), 0.35-0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 504.10 [M+H] ⁺ .

Step 3: Compound 2-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of Carboxylamido)methyl) -N , N -Dimethylisonicotinamide

The compound 2-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)isonicotinic acid (92 mg, 0.18 mmol), dimethylamine hydrochloride (71 mg, 0.87 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide The hydrochloride (76 mg, 0.40 mmol) and N -hydroxy-7-azabenzotriazole (46 mg, 0.34 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C, added with N , N -diisopropylethylamine (0.2 mL, 1.0 mmol), stirred at room temperature for 18 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed , and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 71 mg of white solid with a yield of 73%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.59 (d, J = 5.0 Hz, 1H), 7.55 (s, 1H), 7.32 (d, J = 5.0 Hz, 1H), 7.05-7.12 (m, 2H), 6.92-6.94 (m, 1H), 6.75 (t, J _FH = 75.7 Hz, 1H), 4.49-4.61 (m, 3H), 4.09-4.13 (m, 1H), 3.94 (d, J = 6.8 Hz, 2H), 3.63-3.68 (m, 1H), 3.48-3.54 (m, 1H), 3.12 (s, 3H), 2.96 (s, 3H), 2.66-2.73 (m, 1H), 2.15 (s, 3H), 2.05-2.13 (m, 1H), 1.26-1.33 (m, 1H), 0.63-0.66 (m, 2H), 0.37-0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 531.25 [M+H] ⁺ .

Example 30: Compound 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methane yl) -N , N -lutidine pyridylamine dihydrochloride

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

The compound ( 2R )-1-tert-butyl-2-methyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2 -Dicarboxylate (362 mg, 0.82 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and water (5 mL), then lithium hydroxide monohydrate (176 mg, 4.2 mmol) was added, and the reaction was carried out at 50 °C for 2.5 h After stopping, adding hydrochloric acid to adjust the pH of the solution to 4, and then extracting with ethyl acetate (10 mL × 3). The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 338 mg of white solid with a yield of 96%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.10 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.88-6.90 (m, 1H), 6.73 (t, J _FH = 75.7 Hz, 1H), 4.31 – 4.37 (m, 1H), 3.92 – 3.99 (m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.35 – 3.45 (m, 2H), 2.69 – 2.74 ( m, 1H), 1.87 – 1.96 (m, 1H), 1.44 – 1.46 (m, 9H), 1.29-1.36 (m, 1H), 0.62-0.66 (m, 2H), 0.37-0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 450.20 [M+Na] ⁺ .

Step 2: Compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((6-(dimethylaminocarboxy) Synthesis of tert-butyl)pyridin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate

The compound ( 2R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid ( 334 mg, 0.78 mmol), 6-(aminomethyl) -N , N -lutidine dihydrochloride (238 mg, 0.94 mmol), 1-ethyl-(3-dimethylaminopropyl) yl)carbodiimide hydrochloride (746 mg, 3.89 mmol) and N -hydroxy-7-azabenzotriazole (162 mg, 1.19 mmol) were dissolved in dichloromethane (10 mL), 0 N , N -diisopropylethylamine (0.8 mL, 5.0 mmol) was added dropwise to this solution at ℃, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), and then extracted with dichloromethane (5 mL × 3 ), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 356 mg of a light yellow viscous solid, Yield 77%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.75 – 7.81 (m, 1H), 7.49 – 7.57 (m, 1H), 7.33 – 7.40 (m, 1H), 7.11 (d, J = 8.1 Hz , 1H), 6.80 – 6.86 (m, 2H), 6.61 (t, J _FH = 75.7 Hz, 1H), 4.60 – 4.70 (m, 2H), 4.34 – 4.49 (m, 1H), 4.02 – 4.24 (m, 1H), 3.87 (d, J = 6.8 Hz, 2H), 3.37 – 3.36 (m, 2H), 3.15 (s, 3H), 3.06 (s, 3H), 2.61 – 2.75 (m, 1H), 2.15 – 2.39 (m, 1H), 1.38 – 1.49 (m, 9H), 1.27 – 1.36 (m, 1H), 0.64 – 0.68 (m, 2H), 0.35 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 589.20 [M+H] ⁺ .

Step 3: Compound 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl Synthesis of ) -N , N -lutidine pyridylamine dihydrochloride

The compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((6-(dimethylcarbamoyl) Pyridin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate tert-butyl ester (350 mg, 0.59 mmol) was dissolved in methanol (5 mL) solution, 4 mol/L HCl in ethyl acetate was added The ester solution (5 mL) was stirred at room temperature for 2 h, and the solvent was removed to obtain 332 mg of a white solid with a yield of 97%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.08 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 8.2 Hz, 1H) ), 7.08 (s, 1H), 6.93 (d, J = 9.9 Hz, 1H), 6.76 (t, J _FH = 75.5 Hz, 1H), 4.64-4.73 (m, 2H), 4.55-4.60 (m, 1H) ), 3.94 (d, J = 6.9 Hz, 2H), 3.78-3.83 (m, 1H), 3.66-3.76 (m, 1H), 3.34-3.42 (m, 1H), 3.10 (s, 3H), 3.02 ( s, 3H), 2.89-2.97 (m, 1H), 2.12-2.21 (m, 1H), 1.28-1.37 (m, 1H), 0.63-0.67 (m, 2H), 0.37-0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 489.30 [M+H-2HCl] ⁺ .

Example 31: 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-ethylpyrrolidine-2-methyl (acylamino)methyl) -N , N -lutidamide; and

和實施例32：

Example 32: 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-vinylpyrrolidine-2-methyl Acrylamido)methyl) -N , N -lutidamide Example 31:

and Example 32:

Compound 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl)- N , N -lutidyl pyridamide dihydrochloride (74 mg, 0.13 mmol) and p-toluenesulfonic acid (4 mg, 0.023 mmol) were dissolved in ethanol (3 mL) solution, and 40% acetaldehyde in water was added ( 0.15 mL), heated at 50 °C for 50 min, cooled and added to sodium borohydride to continue the reaction for 2 h, removed the solvent, added water (3 mL), extracted with ethyl acetate (5 mL × 3), dried over anhydrous sodium sulfate, concentrated After separation by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1), 6-((( 2R )-4-(3-(cyclopropylmethoxy) was obtained )-4-(difluoromethoxy)phenyl)-1-ethylpyrrolidine-2-carbamoylamino)methyl) -N , N -lutidyl pyridamide (Example 31), pale yellow Sticky solid 26 mg, 38% yield, and 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-ethene acyl pyrrolidine-2-yl) methyl) - N, N - dimethyl pyridine Amides (Example 32), as a pale yellow viscous solid was 12 mg, 17% yield.

Example 31:

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H) , 7.05 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 6.3 Hz, 1H), 6.83 (s, 1H), 6.60 (t, J _FH = 75.7 Hz, 1H), 4.51-4.68 (m , 2H), 3.84 (d, J = 6.9 Hz, 2H), 3.32-3.40 (m, 2H), 3.24-3.30 (m, 1H), 3.13 (s, 3H), 3.03 (s, 3H), 2.88- 2.97 (m, 1H), 2.71-2.81 (m, 2H), 2.48-2.59 (m, 1H), 2.22-2.25 (m, 1H), 1.28-1.37 (m, 1H), 1.13 (t, J = 7.1 Hz, 3H), 0.62-0.66 (m, 2H), 0.32-0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 517.20 [M+H] ⁺ .

Example 32:

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.78 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H) , 7.11 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 6.81 (d, J = 6.3 Hz, 1H), 6.62 (t, J _FH = 75.7 Hz, 1H), 5.30-5.45 (m , 1H), 4.76-4.88 (m, 2H), 4.42 (d, J = 15.8 Hz, 1H), 3.93-3.97 (m, 1H), 3.88 (d, J = 6.8 Hz, 2H), 3.36-3.45 ( m, 1H), 3.13-3.21 (m, 1H), 3.13 (s, 3H), 3.05 (s, 3H), 2.58-2.68 (m, 2H), 2.19-2.25 (m, 1H), 2.00-2.05 ( m, 1H), 1.28-1.37 (m, 1H), 0.64-0.69 (m, 2H), 0.36-0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 515.35 [M+H] ⁺ .

Example 33: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -ethylpyridamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.2 mmol), ethylamine hydrochloride (163 mg, 2.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (192 mg, 1.0 mmol) and N -hydroxy-7-azabenzotriazole (41 mg, 0.3 mmol) were dissolved in dichloromethane (5 mL) and added dropwise to this solution at 0°C N , N -diisopropylethylamine (0.4 mL, 2.0 mmol), reacted at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was dried over anhydrous sodium sulfate , the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 58 mg of white solid with a yield of 55%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.00 (br.s, 1H), 8.65 (s, 1H), 8.12 (d, J = 7.1 Hz, 1H), 7.82 (br.s, 1H) ), 7.38 (d, J = 7.1 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.87 – 6.93 (m, 2H), 6.62 (t, J _FH = 75.7 Hz, 1H), 4.81 – 4.86 (m, 1H), 4.58 – 4.71 (m, 2H), 3.91 – 4.00 (m, 1H), 3.89 (d, J = 7.3 Hz, 2H), 3.49 – 3.67 (m, 2H), 3.44 – 3.50 ( m, 1H), 3.29 – 3.38 (m, 1H), 2.77 – 2.86 (m, 1H), 2.47 – 2.55 (m, 1H), 2.18 (s, 3H), 1.26 – 1.35 (m, 4H), 0.61 – 0.70 (m, 2H), 0.32 – 0.39 (m, 2H).

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

Example 34: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N , N -diethylpyridamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.2 mmol), diethylamine (73 mg, 1.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 192 mg, 1.0 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.3 mmol) were dissolved in dichloromethane (5 mL), and N was added dropwise to this solution at 0°C, N -diisopropylethylamine (0.17 mL, 1.0 mmol), reacted at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, removed The solvent and the concentrated solution were separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 63 mg of white solid with a yield of 56%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 (t, J = 7.6 Hz, 1H), 7.48 (br.s, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.37 ( d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.90 (s, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.62 (t, J _FH = 75.5 Hz , 1H), 4.55 – 4.61 (m, 3H), 3.93 – 3.97 (m, 1H), 3.88 (d, J = 6.8 Hz, 2H), 3.56 – 3.62 (m, 3H), 3.27 – 3.38 (m, 3H) ), 3.55 – 3.62 (m, 1H), 2.39 – 2.49 (m, 1H), 2.14 (s, 3H), 1.26 – 1.35 (m, 1H), 1.28 (t, J = 6.7 Hz, 3H), 1.18 ( t, J = 6.7 Hz, 3H), 0.64 – 0.69 (m, 2H), 0.35 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 559.30 [M+H] ⁺ .

Example 35: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxamido)methyl) -N , N -dipropylpyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.2 mmol), di-n-propylamine (64 mg, 0.63 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 192 mg, 1.0 mmol) and N -hydroxy-7-azabenzotriazole (42 mg, 0.3 mmol) were dissolved in dichloromethane (5 mL), and N was added dropwise to this solution at 0°C, N -diisopropylethylamine (0.17 mL, 1.0 mmol), reacted at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, removed The solvent and the concentrated solution were separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 76 mg of white solid with a yield of 65%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 (t, J = 7.7 Hz, 1H), 7.43 (br.s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.37 ( d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.62 (t, J _FH = 75.5 Hz , 1H), 4.50 – 4.62 (m, 3H), 3.93 – 3.98 (m, 1H), 3.88 (d, J = 6.8 Hz, 2H), 3.55 – 3.61 (m, 1H), 3.45 – 3.49 (m, 2H) ), 3.32 – 3.39 (m, 1H), 3.19 – 3.25 (m, 2H), 2.55 – 2.62 (m, 1H), 2.40 – 2.48 (m, 1H), 2.15 (s, 3H), 1.58 – 1.62 (m , 2H), 1.26 – 1.35 (m, 1H), 1.00 (t, J = 7.3 Hz, 3H), 0.85 – 0.91 (m, 2H), 0.77 (t, J = 7.3 Hz, 3H), 0.64 – 0.68 ( m, 2H), 0.36 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 587.45 [M+H] ⁺ .

Example 36: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -methyl- N -n-propylpyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (102 mg, 0.2 mmol), N -methyl-n-propylamine (43 mg, 0.6 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt The acid salt (192 mg, 1.0 mmol) and N -hydroxy-7-azabenzotriazole (45 mg, 0.33 mmol) were dissolved in dichloromethane (5 mL), and the solution was added dropwise at 0°C N , N -diisopropylethylamine (0.15 mL, 0.9 mmol) was added, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sodium sulfate After drying, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 59 mg of a white solid with a yield of 52%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 (t, J = 7.1 Hz, 1H), 7.36 – 7.49 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H), 6.90 ( s, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.62 (t, J _FH = 75.4 Hz, 1H), 4.47 – 4.67 (m, 3H), 3.90 – 3.98 (m, 1H), 3.88 ( d, J = 6.5 Hz, 2H), 3.52 – 3.60 (m, 2H), 3.25 – 3.39 (m, 2H), 3.10 (s, 1.5H), 3.00 (s, 1.5H), 2.52 – 2.63 (m, 1H), 2.38 – 2.50 (m, 1H), 2.14 (s, 3H), 1.58 – 1.74 (m, 2H), 1.26 – 1.35 (m, 1H), 0.94 – 1.04 (m, 1.5H), 0.72 – 0.81 (m, 1.5H), 0.62 – 0.70 (m, 2H), 0.33 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 559.20 [M+H] ⁺ .

Example 37: Compound (2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) - N - (3- (two Methylformamide)benzyl)pyrrolidine-2-formamide

Step 1: Compound 3-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of methyl formamido)methyl)benzoate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (83 mg, 0.22 mmol), methyl 3-(aminomethyl)benzoate (97 mg, 0.48 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (93 mg, 0.48 mmol) and N -hydroxy-7-azabenzotriazole (47 mg, 0.34 mmol) were dissolved in dichloromethane (6 mL), to this solution was added dropwise N , N -dichloromethane at 0°C Isopropylethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 5 h, added water (50 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution Silica gel column chromatography was performed (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 81 mg of a colorless liquid with a yield of 70%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.98 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.47 (t , J = 7.7 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 6.92-6.93 (m, 1H), 6.74 (t, J _FH = 73.6 Hz, 1H), 4.57-4.64 (m, 1H), 4.49 (s, 2H), 4.08-4.12 (m, 1H), 3.92 (d, J = 6.9 Hz, 2H), 3.89 (s, 3H), 3.62-3.67 (m, 1H), 3.47-3.51 (m, 1H), 2.65-2.72 (m, 1h), 2.15 (s, 3H), 2.01-2.12 (m, 1H), 1.32-1.36 (m, 1H), 0.62-0.65 ( m, 2H), 0.35-0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 517.20 [M+H] ⁺ .

Step 2: Compound 3-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of formamido)methyl)benzoic acid

The compound 3-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)methyl benzoate (78 mg, 0.15 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL) and water (2 mL), added lithium hydroxide monohydrate (32 mg, 0.76 mmol), 50 ° C The reaction was stopped after 2 h, hydrochloric acid was added to adjust the pH of the solution to 1, extracted with ethyl acetate (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 70 mg of a white solid with a yield of 94%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.51 (t, J = 5.8 Hz, 1H), 7.79-7.88 (m, 2H), 7.50-7.56 (m, 1H), 7.42-7.47 (m, 1H), 7.09-7.13 (m, 1H), 7.05 (s, 1H), 7.02 (t, J _FH = 74.9 Hz, 1H), 6.88 (d, J = 9.6 Hz, 1H), 4.30-4.38 (m, 3H), 4.04-4.08 (m, 1H), 3.89 (d, J = 6.9 Hz, 2H), 3.40-3.50 (m, 2H), 2.56-2.62 (m, 1H), 2.02 (s, 3H) ), 1.84-1.92 (m, 1H), 1.26-1.32 (m, 1H), 0.54-0.59 (m, 2H), 0.32-0.35 (m, 2H).

MS (ESI, pos.ion) m/z: 503.10 [M+H] ⁺ .

Step 3: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (3-(dimethyl) Synthesis of carboxamide)benzyl)pyrrolidine-2-carboxamide

The compound 3-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)benzoic acid (71 mg, 0.14 mmol), dimethylamine hydrochloride (67 mg, 0.82 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide The acid salt (76 mg, 0.40 mmol) and N -hydroxy-7-azabenzotriazole (42 mg, 0.31 mmol) were dissolved in dichloromethane (6 mL), and the solution was added dropwise at 0°C Add N , N -diisopropylethylamine (0.2 mL, 1.0 mmol), stir at room temperature for 15 h, add water (50 mL), extract with dichloromethane (5 mL × 3), and dry the organic phase with anhydrous sodium sulfate , the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 54 mg of white solid with a yield of 72%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.49 (t, J = 5.6 Hz, 1H), 7.33-7.38 (m, 2H), 7.28-7.32 (m, 1H), 7.23-7.27 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 7.03 (t, J _FH = 74.9 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.31-4.37 (m, 2H), 4.04-4.08 (m, 1H), 3.90 (d, J = 6.8 Hz, 2H), 3.41-3.51 (m, 2H), 2.96 (s, 3H), 2.88 (s, 3H), 2.55-2.62 (m, 1H), 2.02 (s, 3H), 1.82-1.91 (m, 1H), 1.23-1.35 (m, 1H), 0.54-0.60 (m, 2H), 0.31-0.35 ( m, 2H).

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

Example 38: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N , N -diisopropylpyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (92 mg, 0.18 mmol), N , N -diisopropylamine (89 mg, 0.88 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Imine hydrochloride (143 mg, 0.75 mmol) and N -hydroxy-7-azabenzotriazole (81 mg, 0.60 mmol) were dissolved in dichloromethane (6 mL) and added to this solution at room temperature N , N -diisopropylethylamine (0.4 mL, 2.0 mmol) was added dropwise to it, stirred at room temperature for 5 h, added with water (50 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sulfuric acid The solution was dried over sodium, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 51 mg of white solid with a yield of 47%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.60 (t, J = 5.8 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.24-7.30 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.06 (s, 1H), 7.03 (t, J _FH = 74.8 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 4.33-4.42 (m, 3H), 4.05-4.09 (m, 1H), 3.90 (d, J = 6.8 Hz, 2H), 3.55-3.65 (m, 2H), 3.39-3.52 (m , 2H), 2.56-2.65 (m, 1H), 2.03 (s, 3H), 1.89-1.99 (m, 1H), 1.43 (d, J = 5.7 Hz, 6H), 1.24-1.27 (m, 1H), 1.09 (d, J = 6.1 Hz, 6H), 0.54-0.60 (m, 2H), 0.30-0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 587.45 [M+H] ⁺ .

Example 39: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -ethyl- N -picolinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (102 mg, 0.20 mmol), N -ethylmethylamine (59 mg, 1.00 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide The hydrochloride salt (198 mg, 1.03 mmol) and N -hydroxy-7-azabenzotriazole (46 mg, 0.34 mmol) were dissolved in dichloromethane (5 mL) and added to this solution at 0°C N ,N -diisopropylethylamine (0.17 mL, 1.00 mmol) was added dropwise, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sulfuric acid The solution was dried over sodium, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 28 mg of a pale yellow solid with a yield of 25%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.77 (t, J = 7.6 Hz, 1H), 7.36 – 7.46 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.90 ( s, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.62 (t, J _FH = 75.4 Hz, 1H), 4.49 – 4.67 (m, 3H), 3.91 – 3.97 (m, 1H), 3.88 ( d, J = 6.9 Hz, 2H), 3.55 – 3.63 (m, 2H), 3.30 – 3.39 (m, 2H), 3.11 (s, 2H), 3.01 (s, 1H), 2.54 – 2.62 (m, 1H) , 2.41 – 2.49 (m, 1H), 2.14 (s, 3H), 1.26 – 1.35 (m, 1H), 1.20 (t, J = 7.0 Hz, 3H), 0.63 – 0.70 (m, 2H), 0.35 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 545.30 [M+H] ⁺ .

Example 40: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N , N -di-n-butylpyridinamide

Compound 6-(((2R)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino )methyl)picolinic acid (97 mg, 0.19 mmol), di-n-butylamine (57 mg, 0.44 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (41 mg, 0.30 mmol) were dissolved in dichloromethane (5 mL), to this solution was added dropwise N at 0°C , N -diisopropylethylamine (0.16 mL, 0.97 mmol), reacted at room temperature for 12 h, washed with water (15 mL), then extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, The solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 41 mg of white solid with a yield of 35%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.1 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H) ,7.13 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.62 (t, J _FH = 75.5 Hz, 1H), 4.54 – 4.67 (m , 3H), 3.93 – 3.99 (m, 1H), 3.89 (d, J = 6.7 Hz, 2H), 3.55 – 3.61 (m, 1H), 3.49 – 3.52 (m, 2H), 3.31 – 3.39 (m, 1H) ), 3.25 – 3.29 (m, 2H), 2.53 – 2.63 (m, 1H), 2.41 – 2.49 (m, 1H), 2.15 (s, 3H), 1.63 – 1.73 (m, 2H), 1.51 – 1.59 (m , 2H), 1.39 – 1.47 (m, 2H), 1.26 – 1.34 (m, 1H), 1.13 – 1.19 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H), 0.64 – 0.70 (m, 2H), 0.35 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 615.35 [M+H] ⁺ .

Example 41: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (2- (dimethylamino) ethyl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), N ¹ , N ¹ , N ² -trimethylethylenediamine (60 mg, 0.59 mmol), 1-ethyl-(3-dimethylamino) propyl)carbodiimide hydrochloride (191 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (56 mg, 0.41 mmol) were dissolved in dichloromethane (5 mL), Cool to 0°C, add N , N -diisopropylethylamine (152 mg, 1.18 mmol), react at room temperature for 4.5 h, add water (30 mL) and stir for 5 min, separate the organic phase, and extract the aqueous phase with dichloromethane (10 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 24/1) to obtain a white Solid 55 mg, yield 47%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.71 – 7.79 (m, 1H), 7.44 – 7.53 (m, 1H), 7.37 – 7.40 (m, 1H), 7.10 (d, J = 8.1 Hz , 1H), 6.87 (s, 1H), 6.83 (d, J = 8.2, Hz, 1H), 6.60 (t, J _FH = 75.6 Hz, 1H), 4.46 – 4.63 (m, 2H), 3.90 – 3.94 ( m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.67 – 3.70 (m, 1H), 3.57 (d, J = 10.6 Hz, 1H), 3.48 – 3.51 (m, 1H), 3.20 – 3.37 (m, 2H), 3.12 (s, 1.5H), 3.03 (s, 1.5H), 2.52 – 2.64 (m, 3H), 2.37 – 2.42 (m, 1H), 2.32 (s, 3H), 2.13 (s , 3H), 2.11 (s, 3H), 1.21 – 1.28 (m, 1H), 0.62 – 0.67 (m, 2H), 0.33 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 588.30 [M+H] ⁺ .

Example 42: Compound 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-propionylpyrrolidine-2 -Carboxylamido)methyl) -N , N -lutidyl pyridinamide

Propionic acid (33 mg, 0.45 mmol), 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N , N -lutidine dihydrochloride (70 mg, 0.12 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (121 mg, 0.63 mmol) and N -hydroxy-7-azabenzotriazole (32 mg, 0.24 mmol) were dissolved in dichloromethane (8 mL) and added to this solution at 0°C N , N -diisopropylethylamine (0.1 mL, 0.6 mmol) was added dropwise to it, stirred at room temperature for 19 h, water (15 mL) was added, extracted with dichloromethane (10 mL × 3), the organic phase was washed with anhydrous sulfuric acid The solution was dried over sodium, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 41 mg of white solid with a yield of 60%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.77 (t, J = 7.3 Hz, 1H), 7.52 (br.s, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.37 ( d, J = 7.3 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.90 (s, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.62 (t, J _FH = 75.4 Hz , 1H), 4.53 – 4.65 (m, 3H), 3.95 – 3.99 (m, 1H), 3.88 (d, J = 6.6 Hz, 2H), 3.52 (t, J = 10.4 Hz, 1H), 3.27 – 3.38 ( m, 1H), 3.14 (s, 3H), 3.06 (s, 3H), 2.52 – 2.64 (m, 1H), 2.32 – 2.49 (m, 3H), 1.27 – 1.33 (m, 1H), 1.17 (t, J = 7.0 Hz, 3H), 0.64 – 0.68 (m, 2H), 0.34 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 545.20 [M+H] ⁺ .

Example 43: Compound 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(2-fluoroacetyl ) pyrrolidine-2-carbamoylamino)methyl) -N , N -lutidyl pyridylamine

2-Fluoroacetic acid (37 mg, 0.47 mmol), 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine -2-Carboxylamido)methyl) -N , N -lutidine dihydrochloride (90 mg, 0.16 mmol), 1-ethyl-(3-dimethylaminopropyl)carboamide Diimine hydrochloride (152 mg, 0.79 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL), and the mixture was heated to 0 °C. N , N -diisopropylethylamine (0.14 mL, 0.85 mmol) was added dropwise to this solution, stirred at room temperature for 7 h, added with water (15 mL), extracted with dichloromethane (10 mL × 3), and the organic phase was After drying over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 73 mg of a white solid with a yield of 83%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.77 (t, J = 7.3 Hz, 1H), 7.57 (br.s, 1H), 7.35 – 7.45 (m, 2H), 7.13 (d, J = 7.8 Hz, 1H), 6.89 (s, 1H), 6.81 – 6.89 (m, 1H), 6.62 (t, J _FH = 75.6 Hz, 1H), 4.91 – 5.05 (m, 2H), 4.55 – 4.68 (m , 3H), 3.93 – 4.02 (m, 1H), 3.88 (d, J = 5.5 Hz, 2H), 3.53 – 3.58 (m, 1H), 3.29 – 3.40 (m, 1H), 3.14 (s, 3H), 3.04 (s, 3H), 2.56 – 2.66 (m, 1H), 2.33 – 2.43 (m, 1H), 1.24 – 1.36 (m, 1H), 0.60 – 0.70 (m, 2H), 0.33 – 0.40 (m, 2H) ).

MS (ESI, pos.ion) m/z: 549.20 [M+H] ⁺ .

Example 44: Compound 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(2,2-difluoro Acetyl)pyrrolidine-2-carbamoylamino)methyl) -N , N -lutidyl pyridinamide

2,2-Difluoroacetic acid (36 mg, 0.38 mmol), 6-((( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl )pyrrolidine-2-carbamoylamino)methyl) -N , N -lutidine dihydrochloride (70 mg, 0.12 mmol), 1-ethyl-(3-dimethylaminopropyl) ) carbodiimide hydrochloride (118 mg, 0.62 mmol) and N -hydroxy-7-azabenzotriazole (32 mg, 0.24 mmol) were dissolved in dichloromethane (8 mL) at 0°C N , N -diisopropylethylamine (0.1 mL, 0.6 mmol) was added dropwise to this solution under conditions, stirred at room temperature for 12 h, added with water (15 mL), extracted with dichloromethane (10 mL × 3), The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 46 mg of white solid, yield 65% .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.77 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 6.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H) , 7.14 (d, J = 7.9 Hz, 1H), 6.89 (s, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.62 (t, J _FH = 75.6 Hz, 1H), 6.08 (t, J _FH = 53.4 Hz, 1H), 4.55 – 4.68 (m, 3H), 4.24 – 4.32 (m, 1H), 3.89 (d, J = 6.7 Hz, 2H), 3.63 (t, J = 11.1 Hz, 1H), 3.32 – 3.44 (m, 1H), 3.15 (s, 3H), 3.04 (s, 3H), 2.60 – 2.69 (m, 1H), 2.35 – 2.43 (m, 1H), 1.27 – 1.39 (m, 1H), 0.64 – 0.69 (m, 2H), 0.36 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 567.30 [M+H] ⁺ .

Example 45: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carbamoylamino)methyl ) -N , N -lutidine pyridamide

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

The compound (R) -1- tert-butyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H -pyrrole-1,2( 2H , 5H )-dicarboxylate (5.6 g, 16.0 mmol), 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene (861 -1-2) (4.79 g, 12.7 mmol), potassium phosphate (8.1 g, 38.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (478 mg, 0.65 mmol) were mixed in dry 1,4-dioxane (60 mL) solution, reacted at 100 °C for 4 h under nitrogen protection, the reaction solution was suction filtered, water (50 mL) was added to the filtrate, and ethyl acetate (25 mL) was added to the filtrate. mL × 3) extraction, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1) to obtain light red Liquid 3.6 g, yield 59%.

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), 5.12 – 5.22 (m, 1H), 5.16 (d, J = 9.1 Hz, 2H), 4.54 – 4.67 (m, 2H) , 3.78 (s, 3H), 1.48 – 1.55 (m, 9H).

MS (ESI, pos.ion) m/z: 498.20 [M+Na] ⁺ .

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

The compound (R) -1- tert-butyl 2-methyl-4- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -1 H - pyrrole -1,2 (2 H , 5H )-dicarboxylate (1.48 g, 3.1 mmol) was dissolved in methanol (30 mL), Pd/C (1.0 g, 10%) was added, and hydrogen was passed through to react at room temperature for 24 h, the catalyst was removed by filtration, and the filtrate was Concentrated to obtain 860 mg of yellow liquid with a yield of 71%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.93 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.99 (t, J _FH = 75.2 Hz, 1H), 6.85 (d, J = 1.8 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 4.26 - 4.30 (m, 1H), 3.84 - 3.88 (m, 1H), 3.69 (s, 2H), 3.66 ( s, 1H), 3.11 - 3.19 (m, 2H), 2.58 - 2.65 (m, 1H), 1.77 - 1.88 (m, 1H), 1.49 (m, 3H), 1.39 (m, 6H).

MS (ESI, pos.ion) m/z: 410.15 [M+Na] ⁺ .

Step 3: Synthesis of compound (2R )-4-(4-(difluoromethoxy)-3-(hydroxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

The compound ( 2R )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-(hydroxy)phenyl)pyrrolidine-1,2-dicarboxylate (860 mg, 2.2 mmol) was dissolved in dichloromethane (3 mL) solution, 4 mol/L HCl in ethyl acetate solution (3 mL) was added, stirred at room temperature for 1 h, and the solvent was removed to obtain a white solid 623 mg, yield 97%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 10.02 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 7.00 (t, J _FH = 75.1 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.79 (dd, J = 8.3, 1.9 Hz, 1H), 4.49 - 4.54 (m, 1H), 3.79 (s, 3H), 3.61 - 3.66 (m, 1H), 3.42 - 3.51 (m, 1H), 3.11 - 3.17 (m, 1H), 2.64 - 2.70 (m, 1H), 1.99-2.10 (m, 1H).

MS (ESI, pos.ion) m/z: 288.10 [M+H-HCl] ⁺ .

Step 4: Synthesis of compound (2R )-1-acetyl-4-(3-(acetyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester

Compound ( 2R )-4-(4-(difluoromethoxy)-3-(hydroxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (269 mg, 0.93 mmol) was dissolved in In methyl chloride (6 mL), N , N -diisopropylethylamine (0.6 mL, 4.0 mmol) was added, acetyl chloride (0.3 mL, 4.0 mmol) was added in an ice bath, and the reaction was stopped after stirring at room temperature for 19 h , water (15 mL) was added, extracted with dichloromethane (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/ v) = 1/2) to obtain 263 mg of pale yellow liquid with a yield of 75%.

MS (ESI, pos.ion) m/z: 372.20 [M+H] ⁺ .

Step 5: Synthesis of compound (2R )-1-acetyl-4-(4-(difluoromethoxy)-3-(hydroxy)phenyl)pyrrolidine-2-carboxylic acid

Compound ( 2R )-1-acetoxy-4-(3-(acetoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (263 mg, 0.71 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (4 mL), lithium hydroxide monohydrate (172 mg, 3.1 mmol) was added, the reaction was stopped after 2 h at 50 °C, and concentrated hydrochloric acid was added to adjust the pH of the solution to 1 , extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 213 mg of a pale yellow solid with a yield of 95%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.89 (s, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.99 (t, J _FH = 75.1 Hz, 1H), 6.85 - 6.88 (m, 1H), 6.74 - 6.76 (m, 1H), 4.19 - 4.24 (m, 1H), 4.01 - 4.06 (m, 1H), 3.27 - 3.42 (m, 2H), 2.59 - 2.67 (m, 1H), 2.00 (s, 3H), 1.75 - 1.83 (m, 1H).

MS (ESI, pos.ion) m/z: 316.10 [M+H] ⁺ .

Step 6: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carbamoylamino)methyl) - Synthesis of N , N -lutidyl pyridamide

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid (72 mg, 0.23 mmol), 6-(amino Methyl) -N , N -lutidine dihydrochloride (94 mg, 0.52 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 88 mg, 0.46 mmol) and N -hydroxy-7-azabenzotriazole (61 mg, 0.45 mmol) were dissolved in dichloromethane (6 mL), and N was added dropwise to this solution at 0°C, N -diisopropylethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 4 h, washed with water (50 mL), and then extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, removed The solvent and the concentrated solution were separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 23 mg of white solid with a yield of 21%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.88 (s, 1H), 8.61 (t, J = 5.9 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.46 ( d, J = 7.9 Hz, 1H), 7.32 - 7.40 (m, 1H), 7.03 - 7.07 (m, 1H), 6.99 (t, J _FH = 75.1 Hz, 1H), 6.86 - 6.89 (m, 1H), 6.72 - 6.77 (m, 1H), 4.32 - 4.50 (m, 3H), 4.02 - 4.05 (m, 1H), 3.38 - 3.46 (m, 2H), 2.96 - 2.98 (m, 3H), 2.88 - 2.89 (m , 3H), 2.51 - 2.62 (m, 1H), 2.02 (s, 3H), 1.82 - 1.87 (m, 1H).

MS (ESI, pos.ion) m/z: 477.25 [M+H] ⁺ .

Example 46: Compound 6-((( 2R )-1-Acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl) - N , N -lutidine pyridamide

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

Compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (5.0 g, 14.71 mmol) was dissolved in a mixture of acetonitrile (25 mL) and concentrated hydrochloric acid (10 mL) In the solvent, the reaction was stopped at 80 °C for 6 h, concentrated under reduced pressure, added water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography Separation (eluent: petroleum ether/ethyl acetate (v/v) = 10/1) gave a pale yellow liquid 3.23 g in 76% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.39 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.5, 2.0 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.53 (t, J _FH = 73.2 Hz, 1H), 5.72 (br.s, 1H).

MS (ESI, pos.ion) m/z: 285.90 [M].

Step 2: Synthesis of compound 1,2-bis(difluoromethoxy)-4-iodobenzene

Compound 2-(difluoromethoxy)-5-iodophenol (770 mg, 2.69 mmol) was dissolved in N , N -dimethylformamide (10 mL), and sodium difluorochloroacetate (733 mg, 10 mL) was added. 4.81 mmol) and cesium carbonate (1.6 g, 4.90 mmol), the reaction was stopped after 4 h at 120 °C, water (25 mL) was added, extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain Light yellow liquid 831 mg, yield 91%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.61 (s, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.53 ( _{t, J FH = 73.1 Hz,} 1H), 6.52 (t, J FH = 73.1 Hz, 1H).

MS (ESI, pos.ion) m/z: 335.90 [M].

Step 3: Compound (R) -1- tert-butyl 2-methyl-4- (3,4-bis (difluoromethoxy) phenyl) -1 H - pyrrole -1,2 (2 H, 5 H )-Dicarboxylate Synthesis

The (R) -1- tert-butyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H - Pyrrole-1,2( 2H , 5H )-dicarboxylate (800 mg, 2.27 mmol), 1,2-bis(difluoromethoxy)-4-iodobenzene (868-1) (790 mg , 2.35 mmol), potassium phosphate (2.0 g, 9.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (35 mg, 0.05 mmol) were mixed in dry 1, 4-dioxane (10 mL) solution was reacted at 100 °C for 2.5 h under nitrogen protection, the reaction solution was suction filtered, water (20 mL) was added to the filtrate, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. It was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 6/1) to obtain 765 mg of brown liquid with a yield of 77%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.25 – 7.31 (m, 3H), 6.56 (t, J _FH = 73.4 Hz, 1H), 6.55 (t, J _FH = 73.4 Hz, 1H), 6.07-6.12 (m, 1H), 5.14-5.23 (m, 1H), 4.49-4.68 (m, 2H), 3.78-3.79 (m, 3H), 1.48 – 1.54 (m, 9H).

MS (ESI, pos.ion) m/z: 458.05 [M+Na] ⁺ .

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

The compound (R) -1- tert-butyl 2-methyl-4- (3,4-bis (difluoromethoxy) phenyl) -1 H - pyrrole -1,2 (2 H, 5 H) - Dicarboxylate (755 mg, 1.74 mmol) was dissolved in methanol (6 mL), Pd/C (76 mg, 10%) was added, hydrogen was passed through it, and the reaction was carried out at room temperature for 19 h. The reaction solution was suction filtered, and the filtrate was concentrated. Silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1) gave 653 mg of a colorless liquid with a yield of 86%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.24 (d, J = 8.3 Hz, 1H), 7.12-7.16 (m, 2H), 6.54 (t, J _FH = 73.5 Hz, 1H), 6.52 (t, J _FH = 73.5 Hz, 1H), 4.34-4.44 (m, 1H), 3.96-4.10 (m, 1H), 3.78 – 3.79 (m, 3H), 3.34-3.46 (m, 2H), 2.67- 2.73 (m, 1H), 2.01-2.09 (m, 1H), 1.45 – 1.49 (m, 9H).

MS (ESI, pos.ion) m/z: 460.20 [M+Na] ⁺ .

Step 5: Synthesis of Compound (2R )-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

Compound ( 2R )-1-tert-butyl 2-methyl 4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (650 mg, 1.49 mmol) was dissolved in dichloromethane (4 mL) solution, 4 mol/L HCl in ethyl acetate solution (6 mL) was added, stirred at room temperature for 1.5 h, and the solvent was removed to obtain 552 mg of pale yellow liquid, yield 98% .

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.28-7.34 (m, 3H), 6.86 (t, J _FH = 73.6 Hz, 1H), 4.62 – 4.64 (m, 1H), 3.90 (s , 3H), 3.81-3.87 (m, 1H), 3.69-3.77 (m, 1H), 3.37 (d, J = 11.0 Hz, 1H), 2.85-2.92 (m, 1H), 2.20-2.29 (m, 1H) ).

MS (ESI, pos.ion) m/z: 338.15 [M+H-HCl] ⁺ .

Step 6: Synthesis of compound (2R )-1-acetoxy-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester

Compound ( 2R )-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride (550 mg, 1.48 mmol) was dissolved in dichloromethane ( 8 mL), N , N -diisopropylethylamine (0.95 mL, 5.70 mmol) was added, acetyl chloride (0.35 mL, 4.90 mmol) was added at 0 °C, the reaction was stopped after stirring at room temperature for 4 h, and water was added. (20 mL) stirred, extracted with dichloromethane (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain 586 mg of pale yellow liquid with a yield of 95%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.24-7.314 (m, 3H), 6.85 (t, J _FH = 73.7 Hz, 1H), 6.81 (t, J _FH = 73.7 Hz, 1H) , 4.46 – 4.51 (m, 1H), 4.09-4.15 (m, 1H), 3.76 (s, 3H), 3.62 (t, J = 8.2 Hz, 1H), 3.57-3.61 (m, 1H), 2.72-2.77 (m, 1H), 2.14 (s, 3H), 2.01-2.07 (m, 1H).

MS (ESI, pos.ion) m/z: 380.10 [M+H] ⁺ .

Step 7: Synthesis of Compound (2R )-1-Acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid

Compound ( 2R )-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester (530 mg, 1.40 mmol) was dissolved in tetrahydrofuran (8 mL) and water (5 mL) in a mixed solvent, lithium hydroxide monohydrate (203 mg, 4.8 mmol) was added, the reaction was stopped after 2 h at 50 °C, and the pH of the solution was adjusted to 6 by adding hydrochloric acid, and extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 552 mg of a white solid with a yield of 92%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.25 – 7.31 (m, 3H), 6.85 (t, J _FH = 73.7 Hz, 1H), 6.81 (t, J _FH = 73.7 Hz, 1H) , 4.44 – 4.49 (m, 1H), 4.11-4.15 (m, 1H), 3.54 – 3.64 (m, 2H), 3.54-3.60 (m, 1H), 2.74-2.81 (m, 1H), 2.14 (s, 3H), 2.00-2.08 (m, 1H).

MS (ESI, pos.ion) m/z: 366.15 [M+H] ⁺ .

Step 8: Compound 6-((( 2R )-1-Acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl)pyridine Synthesis of Ethyl Formate

Compound ( 2R )-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (500 mg, 1.37 mmol), 6-(amino Methyl)picolinate hydrochloride (415 mg, 1.64 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.3 g, 6.80 mmol) and N -Hydroxy-7-azabenzotriazole (280 mg, 2.06 mmol) was dissolved in dichloromethane (15 mL), and N , N -diisopropylethylamine (1.4 mL, 8.5 mmol), react at room temperature for 16 h, add water to wash (10 mL × 3) the organic phase, dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: dichloromethane/methanol). (v/v)=40/1), 482 mg of light yellow solid was obtained, and the yield was 66%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.02 (d, J = 7.6 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H) , 7.48 (br.s, 1H), 7.14 – 7.24 (m, 3H), 6.55 (t, J _FH = 73.5 Hz, 1H), 6.52 (t, J _FH = 73.5 Hz, 1H), 4.61 – 4.76 (m , 3H), 4.47 (q= 7.1 Hz, 2H), 3.99 – 4.04 (m, 1H), 3.62 (t, J = 10.6 Hz, 1H), 3.38 – 3.45 (m, 1H), 2.61 – 2.68 (m, 1H), 2.42 – 2.50 (m, 1H), 2.18 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

MS (ESI, pos.ion) m/z: 528.15 [M+H] ⁺ .

Step 9: Compound 6-((( 2R )-1-Acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl)pyridine Synthesis of Formic Acid

The compound ethyl 6-((( 2R )-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl)picolinate The ester (470 mg, 0.39 mmol) was dissolved in a mixed solvent of tetrahydrofuran (8 mL) and water (5 mL), lithium hydroxide monohydrate (183 mg, 4.36 mmol) was added, the reaction was stopped after 2 h at 50 °C, and the dilution was added. The pH of the solution was adjusted to 6 with hydrochloric acid, extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 426 mg of a white solid with a yield of 95%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.06 (d, J = 7.5 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H) ), 7.26 – 7.32 (m, 3H), 6.85 (t, J _FH = 73.8 Hz, 1H), 6.81 (t, J _FH = 73.8 Hz, 1H), 4.53 – 4.73 (m, 3H), 4.11 – 4.17 ( m, 1H), 3.66 (t, J = 10.9 Hz, 1H), 3.55 – 3.60 (m, 1H), 2.70 – 2.76 (m, 1H), 2.16 (s, 3H), 2.06 – 2.15 (m, 1H) .

MS (ESI, pos.ion) m/z: 500.10 [M+H] ⁺ .

Step 10: Compound 6-((( 2R )-1-Acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl)- Synthesis of N , N -lutidyl pyridamide

The compound 6-((( 2R )-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl)picolinic acid ( 80 mg, 0.16 mmol), dimethylamine hydrochloride (66 mg, 0.81 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.79 mmol) ) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL), and N , N -diisopropyl was added dropwise to this solution at 0°C Ethylamine (0.27 mL, 1.60 mmol), reacted at room temperature for 10 h, washed with water (15 mL), then extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was carried out Separation by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) gave 52 mg of white solid with a yield of 61%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.77 (t, J = 7.7 Hz, 1H), 7.56 (br.s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.38 ( d, J = 7.8 Hz, 1H), 7.13 – 7.25 (m, 3H), 6.56 (t, J _FH = 73.5 Hz, 1H), 6.53 (t, J _FH = 73.5 Hz, 1H), 4.51 – 4.67 (m , 3H), 3.99 (dd, J = 9.9, 7.6 Hz, 1H), 3.58 (t, J = 10.6 Hz, 1H), 3.34 – 3.43 (m, 1H), 3.14 (s, 3H), 3.06 (s, 3H), 2.58 – 2.65 (m, 1H), 2.42 – 2.50 (m, 1H), 2.15 (s, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ (ppm): 171.3, 169.8, 168.8, 156.0, 153.9, 142.4, 141.3, 138.51, 137.7, 125.3, 122.6, 122.2, 121.6, 118.3, 115. , 44.7, 43.3, 39.0, 35.6, 35.5, 22.6.

MS (ESI, pos.ion) m/z: 527.15 [M+H] ⁺ .

Example 47: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Acrylamido)methyl) -N , N -lutidyl pyridamide

Step 1: Compound ( 2R )-1-tert-butyl 2-methyl 4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-di Synthesis of Carboxylic Acid Esters

Compound ( 2R )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-1,2-dicarboxylate (487 mg, 1.25 mmol), potassium carbonate (364 mg, 2.63 mmol) was dissolved in N , N -dimethylformamide (10 mL), to this solution was added cyclopentyl bromide (303 mg, 2.03 mmol) at room temperature , reacted at 70 °C for 5 h, washed with water (50 mL), extracted with ethyl acetate (15 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent). : petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 273 mg of pale yellow liquid with a yield of 47%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.09 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.94 (t, J _FH = 74.8 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 4.91-4.94 (m, 1H), 4.27-4.31 (m, 1H), 3.86-3.93 (m, 1H), 3.69 (s, 2H), 3.66 (s, 1H) ), 3.37-3.45 (m, 1H), 3.18-3.267 (m, 1H), 2.60-2.68 (m, 1H), 1.85-1.93 (m, 3H), 1.66-1.76 (m, 4H), 1.55-1.61 (m, 2H), 1.35-1.40 (m, 9H).

MS (ESI, pos.ion) m/z: 478.30 [M+Na] ⁺ .

Step 2: Synthesis of Compound (2R )-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

The compound ( 2R )-1-tert-butyl 2-methyl 4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylic acid The ester (412 mg, 0.88 mmol) was dissolved in dichloromethane (4 mL) solution, 4 mol/L HCl in ethyl acetate solution (3 mL) was added, stirred at room temperature for 1 h, and the solvent was removed to obtain 269 mg of a colorless liquid , the yield is 76%.

MS (ESI, pos.ion) m/z: 356.20 [M+H-HCl] ⁺ .

Step 3: Synthesis of compound (2R )-1-acetoxy-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester

Compound ( 2R )-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride (269 mg, 0.76 mmol) It was dissolved in dichloromethane (6 mL), N , N -diisopropylethylamine (0.5 mL, 3.0 mmol) was added, acetyl chloride (0.2 mL, 3.0 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature The reaction was stopped after 4 h, washed with 50 mL of water, extracted with dichloromethane (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate). (v/v) = 1/2), 213 mg of light yellow liquid was obtained, and the yield was 70%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.11 (d, J = 8.3 Hz, 1H), 7.04 - 7.08 (m, 1H), 6.94 (t, J _FH = 74.8 Hz, 1H) , 6.87 (d, J = 8.3, 1.7 Hz, 1H), 4.91 - 4.94 (m, 1H), 4.29 - 4.34 (m, 1H), 4.06 - 4.09 (m, 1H), 3.63 (s, 3H), 3.41 - 3.49 (m, 2H), 2.61 - 2.68 (m, 1H), 2.01 (s, 3H), 1.83 - 1.91 (m, 3H), 1.68 - 1.77 (m, 4H), 1.54 - 1.62 (m, 2H) .

MS (ESI, pos.ion) m/z: 398.25 [M+H] ⁺ .

Step 4: Synthesis of Compound (2R )-1-Acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid

The compound ( 2R )-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate methyl ester (213 mg, 0.54 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (3 mL), lithium hydroxide monohydrate (113 mg, 2.69 mmol) was added, the reaction was stopped at 50 °C for 2 h, and hydrochloric acid was added to adjust the pH of the solution to 1 , extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 197 mg of pale yellow liquid, with a yield of 96%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.11 (d, J = 8.3 Hz, 1H), 7.04 - 7.08 (m, 1H), 6.95 (t, J _FH = 74.8 Hz, 1H) , 6.87 (d, J = 8.3, 1.7 Hz, 1H), 4.91 - 4.94 (m, 1H), 4.21 - 4.25 (m, 1H), 4.03 - 4.10 (m, 1H), 3.40 - 3.49 (m, 2H) , 2.63 - 2.69 (m, 1H), 2.01 (s, 3H), 1.82 - 1.95 (m, 3H), 1.67 - 1.78 (m, 4H), 1.53 - 1.63 (m, 2H).

MS (ESI, pos.ion) m/z: 384.10 [M+H] ⁺ .

Step 5: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate The synthesis of amino) methyl) picolinate ethyl ester

Compound ( 2R )-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (197 mg, 0.51 mmol) ), ethyl 6-(aminomethyl)picolinate hydrochloride (164 mg, 0.76 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (213 mg, 1.11 mmol) and N -hydroxy-7-azabenzotriazole (106 mg, 0.78 mmol) were dissolved in dichloromethane (6 mL), to this solution was added dropwise N , N -diiso Propylethylamine (0.6 mL, 4.0 mmol), stirred at room temperature for 7 h, washed with water (50 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution Silica gel column chromatography was performed (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 231 mg of a pale yellow solid with a yield of 82%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.65-8.68 (m, 1H), 7.90 - 7.98 (m, 2H), 7.67 (d, J = 7.3 Hz, 1H), 7.11 (d , J = 8.3 Hz, 1H), 7.04 - 7.06 (m, 1H), 6.95 (t, J _FH = 74.8 Hz, 1H), 6.87 - 6.89 (m, 1H), 4.85 - 4.90 (m, 1H), 4.29 - 4.52 (m, 5H), 4.04 - 4.10 (m, 1H), 3.44 - 3.56 (m, 2H), 2.60 - 2.67 (m, 1H), 2.04 (s, 3H), 1.85 - 1.94 (m, 3H) , 1.66 -1.78 (m, 4H), 1.52 - 1.62 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H)

MS (ESI, pos.ion) m/z: 546.30 [M+H] ⁺ .

Step 6: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Synthesis of Amino)methyl)picolinic acid

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino) Methyl)picolinate (231 mg, 0.42 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (4 mL), and then lithium hydroxide monohydrate (96 mg, 1.71 mmol) was added, and the reaction was carried out at 50 °C After 2 h, the solution was stopped, and hydrochloric acid was added to adjust the pH of the solution to 1. The solution was extracted with ethyl acetate (5 mL × 3). The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 215 mg of a pale yellow solid with a yield of 98%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.67 (t, J = 6.0 Hz, 1H), 7.90 - 7.96 (m, 2H), 7.65 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.08 - 7.24 (m, 1H), 6.95 (t, J _FH = 74.8 Hz, 1H), 6.87-6.90 (m, 1H), 4.88 - 4.92 (m, 1H) ), 4.35 - 4.53 (m, 3H), 4.08 - 4.10 (m, 1H), 3.43 - 3.52 (m, 2H), 2.60 - 2.67 (m, 1H), 2.04 (s, 3H), 1.85 - 1.94 (m , 3H), 1.67 - 1.77 (m, 4H), 1.54 - 1.63 (m, 2H).

MS (ESI, pos.ion) m/z: 518.25 [M+H] ⁺ .

Step 7: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Synthesis of Amino)methyl) -N , N -lutidyl pyridamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino) Methyl)picolinic acid (76 mg, 0.15 mmol), dimethylamine hydrochloride (45 mg, 1.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 86 mg, 0.45 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.31 mmol) were dissolved in dichloromethane (6 mL), to this solution was added dropwise N , N at room temperature -Diisopropylethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 20 h, washed with water (50 mL), then extracted with dichloromethane (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed , and the concentrated solution was subjected to column separation (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 37 mg of white solid with a yield of 46%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.56 - 8.86 (m, 1H), 7.80 - 7.92 (m, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.32 - 7.41 (m, 1H), 7.01 - 7.15 (m, 2H), 6.95 (t, J _FH = 74.8 Hz, 1H), 6.82 - 6.91 (m, 1H), 4.84 - 4.97 (m, 1H), 4.30 - 4.52 ( m, 3H), 4.02 - 4.26 (m, 1H), 3.39 - 3.57 (m, 2H), 2.98 (s, 3H), 2.91 (s, 3H), 2.56 - 2.71 (m, 1H), 2.04 (s, 3H), 1.83 - 1.94 (m, 3H), 1.67 - 1.77 (m, 4H), 1.54 - 1.63 (m, 2H).

MS (ESI, pos.ion) m/z: 545.30 [M+H] ⁺ .

Example 48: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-(ethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl) -N , N -lutidine

Step 1: Compound ( 2R )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-1,2-dicarboxylate Synthesis

Compound ( 2R )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrole-1,2-dicarboxylate (489 mg, 1.26 mmol), potassium carbonate (364 mg, 2.63 mmol) was dissolved in N , N -dimethylformamide (10 mL), to this solution was added iodoethane (0.2 mL, 3.0 mmol) at room temperature, 70 The reaction was carried out at ℃ for 3 h, washed with water (50 mL), and then extracted with ethyl acetate (5 mL × 3). The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 323 mg of pale yellow liquid with a yield of 62%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.10 (d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 7.01 (t, J _FH = 74.9 Hz, 1H), 6.86 (dd, J = 8.3, 1.7 Hz, 1H), 4.26 - 4.32 (m, 1H), 4.10 (q, J = 7.0 Hz, 2H), 3.85 - 3.95 (m, 1H), 3.65 - 3.72 (m, 3H) ), 3.39 - 3.47 (m, 1H), 3.16 - 3.26 (m, 1H), 2.58 - 2.69 (m, 1H), 1.88 - 2.00 (m, 1H), 1.39 - 1.40 (m, 3H), 1.33 - 1.35 (m, 9H).

MS (ESI, pos.ion) m/z: 438.20 [M+Na] ⁺ .

Step 2: Synthesis of compound (2R )-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride

The compound ( 2R )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-1,2-dicarboxylate (323 mg, 0.58 mmol) was dissolved in dichloromethane (4 mL) solution, 4 mol/L HCl in ethyl acetate solution (3 mL) was added, stirred at room temperature for 1 h, and the solvent was removed to obtain 175 mg of pale yellow liquid, which was collected rate of 94%.

MS (ESI, pos.ion) m/z: 316.10 [M+H-HCl] ⁺ .

Step 3: Synthesis of Compound (2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride

Compound ( 2R )-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride (175 mg, 0.56 mmol) was dissolved in two In methyl chloride (6 mL), N , N -diisopropylethylamine (0.3 mL, 2.0 mmol) was added, and acetyl chloride (0.1 mL, 1.0 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction was stopped, water (50 mL) was added to the organic phase, the aqueous phase was extracted with dichloromethane (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ Ethyl acetate (v/v) = 1/2) to obtain light yellow liquid 166 mg, yield 84%.

MS (ESI, pos.ion) m/z: 358.10 [M+H] ⁺ .

Step 4: Synthesis of compound (2R )-1-acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylic acid

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride (166 mg, 0.46 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (3 mL), then lithium hydroxide monohydrate (113 mg, 2.69 mmol) was added, the reaction was stopped after 2 h at 50 °C, and hydrochloric acid was added to adjust the pH of the solution = 1, and then extracted with ethyl acetate (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 149 mg of light yellow liquid, the yield was 93%.

MS (ESI, pos.ion) m/z: 344.20 [M+H] ⁺ .

Step 5: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-(ethoxy)phenyl)pyrrolidine-2-carbamoylamino )methyl) -N , N -lutidyl pyridamide synthesis

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-(ethoxy)phenyl)pyrrolidine-2-carboxylic acid (67 mg, 0.20 mmol) , 6-(aminomethyl) -N , N -lutidylpyridamide dihydrochloride (96 mg, 0.54 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (88 mg, 0.46 mmol) and N -hydroxy-7-azabenzotriazole (56 mg, 0.41 mmol) were dissolved in dichloromethane (6 mL) and added to this solution at room temperature N , N -diisopropylethylamine (0.3 mL, 2.0 mmol) was added dropwise, stirred at room temperature for 16 h, washed with water (50 mL), then extracted with dichloromethane (5 mL × 3), the organic phase was washed with anhydrous sulfuric acid After drying over sodium, the solvent was removed, and the concentrated solution was subjected to column separation (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 56 mg of a white solid with a yield of 57%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.61 - 8.83 (m, 1H), 7.81 - 7.92 (m, 1H), 7.31 - 7.52 (m, 2H), 7.04 - 7.16 (m, 1H) 2H), 7.01 (t, J _FH = 74.8 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 4.29 - 4.56 (m, 3H), 3.99 - 4.21 (m, 3H), 3.39 - 3.56 ( m, 2H), 2.97 (s, 3H), 2.90 (s, 3H), 2.54-2.69 (m, 1H), 2.03 (s, 3H), 1.81 - 1.90 (m, 1H), 1.28 - 1.38 (m, 3H).

MS (ESI, pos.ion) m/z: 505.20 [M+H] ⁺ .

Example 49: Compound 6-(( 2R- 1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl acyl amino) methyl) - N, N - dimethyl - d ₆ - pyridin Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate amino) methyl) pyridine-carboxylic acid (90 mg, 0.18 mmol), N, N - dimethyl - d ₆ - amine hydrochloride (77 mg, 0.88 mmol), 1- ethyl - (3-dimethylaminopropyl propyl)carbodiimide hydrochloride (173 mg, 0.9 mmol) and N -hydroxy-7-azabenzotriazole (48 mg, 0.35 mmol) were dissolved in dichloromethane (5 mL), N , N -diisopropylethylamine (0.15 mL, 0.91 mmol) was added dropwise to this solution at 0°C, the reaction was carried out at room temperature for 12 h, water (15 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3 ), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 25/1) to obtain a white solid 68 mg, yield 70%.

¹ H NMR (600 MHz, CD ₃ OD) δ (ppm): 7.93 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H) ), 7.12 (d, J = 7.9 Hz, 1H), 7.09 (s, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.75 (t, J _FH = 75.7 Hz, 1H), 4.49 – 4.65 ( m, 3H), 4.10 – 4.13 (m, 1H), 3.94 (d, J = 6.7 Hz, 2H), 3.66 (t, J = 10.5 Hz, 1H), 3.48 – 3.56 (m, 1H), 2.68 – 2.72 (m, 1H), 2.16 (s, 3H), 2.05 – 2.21 (m, 1H), 1.32 – 1.39 (m, 1H), 0.63 – 0.67 (m, 2H), 0.37 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 537.25 [M+H] ⁺ .

Example 50: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethane oxy) phenyl) pyrrolidine-2-acyl-amino) methyl) - N, N - dimethyl - d ₆ - pyridin Amides

Step 1: Compound ( 2R )-1-tert-Butyl 2-methyl 4-(3-(cyclopropyl-(1,1-duteuteto)methoxy)-4-(difluoromethoxy) )Phenyl)pyrrolidine-1,2-dicarboxylate synthesis

( 2R )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-1,2-dicarboxylate (630 mg, 1.63 mmol), 1,1-dideuterated cyclopropylmethanol (247 mg, 3.33 mmol), triphenylphosphine (1.08 g, 14.12 mmol) were dissolved in dry tetrahydrofuran (10 mL) solution, slowly added under ice bath conditions Diisopropyl azodicarboxylate (247 mg, 3.33 mmol) was reacted at room temperature for 4 h, water (20 mL) was added, and then extracted with ethyl acetate (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate and removed. The solvent was concentrated under reduced pressure and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1) to obtain 653 mg of a colorless liquid with a yield of 90%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.12 (d, J = 7.9 Hz, 1H), 6.80 – 6.83 (m, 2H), 6.61 (t, J _FH = 73.6 Hz, 1H), 4.94 – 5.00 (m, 1H), 4.32 – 4.42 (m, 1H), 3.94 – 4.08 (m, 1H), 3.78 – 3.79 (m, 3H), 3.40 – 3.47 (m, 1H), 3.29 – 3.38 (m, 1H), 2.62 – 2.70 (m, 1H), 1.98 – 2.09 (m, 1H), 1.45 – 1.48 (m, 9H), 0.64 – 0.68 (m, 2H), 0.36 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 466.10 [M+Na] ⁺ .

Step 2: Compound ( 2R )-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of Carboxylic Acid Methyl Hydrochloride

The compound (2 R )-1-tert-butyl 2-methyl 4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)benzene yl)pyrrolidine-1,2-dicarboxylate (400 mg, 0.9 mmol) was dissolved in dichloromethane (5 mL) solution, added 4 mol/L HCl in ethyl acetate solution (10 mL), room temperature The reaction was carried out for 3 h, and the solvent was removed to obtain 314 mg of a light yellow viscous solid with a yield of 92%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 8.3, 1.9 Hz , 1H), 6.76 (t, J _FH = 75.5 Hz, 1H), 4.60 – 4.64 (m, 1H), 3.90 (s, 3H), 3.76 – 3.83 (m, 1H), 3.63 – 3.71 (m, 1H) , 3.32 – 3.39 (m, 1H), 2.82 – 2.89 (m, 1H), 2.20 – 2.29 (m, 1H), 1.26 – 1.34 (m, 1H), 0.62 – 0.68 (m, 2H), 0.37 – 0.41 ( m, 2H).

MS (ESI, pos.ion) m/z: 344.10 [M+H-HCl] ⁺ .

Step 3: Compound ( 2R )-1-Acetyl-4-(3-(Cyclopropyl-(1,1-Dideutero)methoxy)-4-(difluoromethoxy)phenyl ) Synthesis of methyl pyrrolidine-2-carboxylate

The compound ( 2R )-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid Methyl ester hydrochloride (343 mg, 0.91 mmol) was dissolved in dichloromethane (10 mL), N , N -diisopropylethylamine (1.0 mL, 6.1 mmol) was added, and acetyl chloride was added at 0°C (0.3 mL, 4.0 mmol), the reaction was stopped after stirring at room temperature for 16 h, an aqueous solution was added to wash the organic phase (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluting Agent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 222 mg of a colorless liquid with a yield of 63%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.15 (d, J = 8.7 Hz, 1H), 6.80 – 6.84 (m, 2H), 6.63 (t, J _FH = 73.6 Hz, 1H), 4.48 – 4.52 (m, 1H), 3.93 – 3.98 (m, 1H), 3.79 (s, 3H), 3.63 (t, J = 10.5 Hz, 1H), 3.38 – 3.47 (m, 2H), 2.64 – 2.71 (m , 1H), 2.13 (s, 3H), 2.02 – 2.07 (m, 1H), 1.27 – 1.33 (m, 1H), 0.65 – 0.70 (m, 2H), 0.36 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 386.50 [M+H] ⁺ .

Step 4: Compound ( 2R )-1-Acetyl-4-(3-(Cyclopropyl-(1,1-Dideutero)methoxy)-4-(difluoromethoxy)phenyl ) Synthesis of pyrrolidine-2-carboxylic acid

The compound ( 2R )-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrole Methyl alkane-2-carboxylate (217 mg, 0.56 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide monohydrate (121 mg, 2.88 mmol) was added, and the reaction was carried out at 50 °C After 1 h, the solution was stopped, diluted hydrochloric acid was added to adjust the pH of the solution to 1, extracted with ethyl acetate (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 208 mg of a light yellow liquid with a yield of 99%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.11 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.90 – 6.93 (m, 1H), 6.74 (t, J _FH = 74.9 Hz, 1H), 4.43 – 4.47 (m, 1H), 4.08 – 4.15 (m, 1H), 3.49 – 3.56 (m, 1H), 3.56 – 3.64 (m, 1H), 2.72 – 2.78 (m, 1H), 2.14 (s, 3H), 2.00 – 2.08 (m, 1H), 1.28 – 1.346 (m, 1H), 0.62 – 0.67 (m, 2H), 0.37 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 372.10 [M+H] ⁺ .

Step 5: Compound 6-((( 2R )-1-Acetyl-4-(3-(Cyclopropyl-(1,1-Dideutero)methoxy)-4-(difluoromethoxy) Synthesis of Ethyl)phenyl)pyrrolidine-2-carbamoylamino)methyl)picolinate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl)pyrrole Alkane-2-carboxylic acid (205 mg, 0.55 mmol), 6-(aminomethyl)picolinate ethyl ester hydrochloride (267 mg, 1.09 mmol), 1-ethyl-(3-dimethylaminopropyl) ) carbodiimide hydrochloride (523 mg, 2.73 mmol) and N -hydroxy-7-azabenzotriazole (158 mg, 1.16 mmol) were dissolved in dichloromethane (10 mL) and cooled to After 0 °C, N , N -diisopropylethylamine (0.7 mL, 4.0 mmol) was added, the reaction was carried out at room temperature for 17 h, water (15 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). Dry over anhydrous sodium sulfate, remove the solvent, concentrate, and conduct silica gel column chromatography separation (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 267 mg of a white viscous solid with a yield of 90%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.02 (d, J = 7.5 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H) , 7.11 (d, J = 8.1 Hz, 1H), 6.89 (s, 1H), 6.86 (dd, J = 8.2, 1.8 Hz, 1H), 6.62 (t, J _FH = 75.7 Hz, 1H), 4.59 – 4.77 (m, 3H), 4.47 (q, J = 7.1 Hz, 2H), 3.95 – 3.99 (m, 1H), 3.62 (t, J = 10.6 Hz, 1H), 3.29 – 3.41 (m, 1H), 2.58 – 2.65 (m, 1H), 2.39 – 2.48 (m, 1H), 2.16 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H), 1.25 – 1.31 (m, 1H), 0.64 – 0.68 (m, 2H), 0.35 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 534.70 [M+H] ⁺ .

Step 6: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy) )Phenyl)pyrrolidine-2-carbamoylamino)methyl)picolinic acid synthesis

Compound 6-(((2 R )-1-acetoxy-4-(3-(cyclopropyl-(1,1-duteuteto)methoxy)-4-(difluoromethoxy) Phenyl)pyrrolidine-2-carbamoylamino)methyl)picolinate (267 mg, 0.5 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide monohydrate was added (101 mg, 2.5 mmol), the reaction was stopped after 1 h at 50 °C, diluted hydrochloric acid was added to adjust the pH of the solution to 6, extracted with ethyl acetate (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 242 mg Pale yellow solid, 95% yield.

MS (ESI, pos.ion) m/z: 506.70 [M+H] ⁺ .

Step 7: Compound 6-((( 2R )-1-Acetyl-4-(3-(Cyclopropyl-(1,1-Dideutero)methoxy)-4-(difluoromethoxy) yl) phenyl) pyrrolidine-2-acyl) methyl) - N, N - dimethyl - d ₆ - synthesis of Amides pyridine

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)benzene yl) pyrrolidine-2-acyl-amino) methyl) pyridine-carboxylic acid (94 mg, 0.18 mmol), N, N - dimethyl - d ₆ - amine hydrochloride (77 mg, 0.88 mmol), 1- ethyl Alkyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (173 mg, 0.91 mmol) and N -hydroxy-7-azabenzotriazole (48 mg, 0.35 mmol) were dissolved in In dichloromethane (5 mL), after cooling to 0 °C, N , N -diisopropylethylamine (0.15 mL, 0.91 mmol) was added, the reaction was carried out at room temperature for 18 h, water (15 mL) was added, and dichloromethane was extracted. (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, concentrated, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 25/1) to obtain a white solid 42 mg, 42% yield.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.90 – 7.95 (m, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 7.1 Hz, 1H), 7.05 – 7.12 (m, 2H), 6.90 (s, 1H), 6.75 (t, J _FH = 75.6 Hz, 1H), 4.48 – 4.65 (m, 3H), 4.07 – 4.15 (m, 1H), 3.63 – 3.69 ( m, 1H), 3.47 – 3.57 (m, 1H), 2.65 – 2.74 (m, 1H), 2.16 (s, 3H), 2.01 – 2.13 (m, 1H), 1.24 – 1.37 (m, 1H), 0.60 – 0.68 (m, 2H), 0.34 – 0.42 (m, 2H).

MS (ESI, pos.ion) m/z: 539.30 [M+H] ⁺ .

Example 51: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -cyclopropylpyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (102 mg, 0.2 mmol), cyclopropylamine (43 mg, 0.6 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.0 mmol) and N -hydroxy-7-azabenzotriazole (45 mg, 0.33 mmol) were dissolved in dichloromethane (5 mL), to this solution was added dropwise N , N at 0°C -Diisopropylethylamine (0.15 mL, 0.9 mmol), reacted at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed , the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 59 mg of white solid with a yield of 52%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.96 (br.s, 1H), 8.77 (br.s, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.83 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.63 (t, J _FH = 75.6 Hz, 1H), 4.85 (t, J = 8.0 Hz, 1H), 4.56 – 4.71 (m, 2H), 3.94 – 4.00 (m, 1H), 3.90 (d, J = 6.7 Hz, 2H), 3.42 – 3.47 (m, 1H), 3.29 – 3.38 (m, 1H), 2.99 – 3.06 (m, 1H), 2.82 – 2.90 (m, 1H), 2.47 – 2.54 (m, 1H), 2.21 (s, 3H), 1.23 – 1.37 (m, 3H), 0.80 – 0.92 (m, 2H), 0.62 – 0.70 (m, 2H), 0.33 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 543.20 [M+H] ⁺ .

Example 52: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -cyclopropyl- N -methylpyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (80 mg, 0.16 mmol), N -methylcyclopropylamine (35 mg, 0.33 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt The acid salt (154 mg, 0.8 mmol) and N -hydroxy-7-azabenzotriazole (33 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL), and the solution was added dropwise at 0°C N , N -diisopropylethylamine (0.15 mL, 0.91 mmol) was added, reacted at room temperature for 5 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sodium sulfate After drying, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 71 mg of white solid, with a yield of 63%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.77 (t, J = 7.4 Hz, 1H), 7.54 (br.s, 1H), 7.42 – 7.44 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.90 (s, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.62 (t, J _FH = 75.6 Hz, 1H) , 4.49 – 4.67 (m, 3H), 3.93 – 3.97 (m, 1H), 3.88 (d, J = 6.8 Hz, 2H), 3.56 (t, J = 10.6 Hz, 1H), 3.27 – 3.38 (m, 1H) ), 3.15 (s, 3H), 2.97 – 3.07 (m, 1H), 2.43 – 2.62 (m, 2H), 2.14 (s, 3H), 1.24 – 1.37 (m, 1H), 0.62 – 0.71 (m, 2H) ), 0.47 – 0.55 (m, 2H), 0.31 – 0.42 (m, 4H).

MS (ESI, pos.ion) m/z: 557.20 [M+H] ⁺ .

Example 53: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Carboxylamido)methyl) -N -cyclohexyl- N -methylpyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (102 mg, 0.20 mmol), N -methylcyclohexylamine (46 mg, 0.41 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide The hydrochloride salt (196 mg, 1.02 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL) and added to this solution at 0°C N ,N -diisopropylethylamine (0.17 mL, 1.00 mmol) was added dropwise, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sulfuric acid The solution was dried over sodium, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 39 mg of white solid with a yield of 32%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.73 – 7.79 (m, 1H), 7.35 – 7.44 (m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 6.90 (s, 1H) ), 6.86 (d, J = 7.0 Hz, 1H), 6.62 (t, J _FH = 75.5 Hz, 1H), 4.48 – 4.67 (m, 3H), 3.90 – 3.98 (m, 1H), 3.88 (d, J = 6.2 Hz, 2H), 3.53 – 3.61 (m, 1H), 3.35 – 3.45 (m, 2H), 3.01 (s, 2H), 2.83(s, 1H), 2.51 – 2.62 (m, 1H), 2.39 – 2.50 (m, 1H), 2.14 (s, 3H), 1.69 – 1.83 (m, 4H), 1.44 – 1.60 (m, 4H), 1.26 – 1.34 (m, 1H), 1.02 – 1.19 (m, 2H), 0.63 – 0.70 (m, 2H), 0.34 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 599.20 [M+H] ⁺ .

Example 54: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -((5-fluoropyridin-2-yl)methyl) -N -methylpyridamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (102 mg, 0.21 mmol), 1-(5-fluoropyridin-2-yl) -N -methylmethanamine (57 mg, 0.41 mmol), 1-ethyl-(3- Dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (40 mg, 0.29 mmol) were dissolved in dichloromethane (5 mL), N , N -diisopropylethylamine (0.17 mL, 1.0 mmol) was added dropwise to this solution at 0 °C, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), and extracted with dichloromethane. (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain a white solid 47 mg, yield 37%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.38 – 8.42 (m, 1H), 7.72 – 7.80 (m, 1H), 7.34 – 7.54 (m, 4H), 7.10 (d, J = 7.7 Hz , 1H), 6.88 (s, 1H), 6.84 (d, J = 7.5 Hz, 1H), 6.60 (t, J _FH = 75.5 Hz, 1H), 4.77 – 4.85 (m, 2H), 4.47 – 4.61 (m , 3H), 3.84 – 3.94 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.46 – 3.56 (m, 1H), 3.26 – 3.36 (m, 1H), 3.10 (s, 3H), 2.40 – 2.56 (m, 2H), 2.11 (s, 3H), 1.24 – 1.34 (m, 1H), 0.61 – 0.66 (m, 2H), 0.31 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 626.20 [M+H] ⁺ .

Example 55: Compound ( 2R )-1-Acetyl- N- (3-(cyclohexyl(methyl)carbamoyl)benzyl)-4-(3-(cyclopropylmethoxy) )-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamide

The compound 3-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)benzoic acid (97 mg, 0.19 mmol), N -methylcyclohexylamine (76 mg, 0.67 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide The hydrochloride salt (103 mg, 0.53 mmol) and N -hydroxy-7-azabenzotriazole (69 mg, 0.50 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C, added with N , N -diisopropylethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 17 h, washed with water (50 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, removed The solvent and the concentrated solution were separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 63 mg of white solid with a yield of 54%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.31-7.38 (m, 2H), 7.16-7.26 (m, 2H), 7.09-7.13 (m, 1H), 7.05 (d, J = 1.6 Hz, 1H), 7.03 (t, J _FH = 74.9 Hz, 1H), 6.87 (d, J = 9.8 Hz, 1H), 4.30-4.35 (m, 3H), 4.04-4.08 (m, 1H), 3.90 (d, J = 6.9 Hz, 2H), 3.37-3.51 (m, 2H), 3.15-3.28 (m, 1H), 2.70-2.82 (m, 3H), 2.55-2.62 (m, 1H), 2.01 (s , 3H), 1.84-1.97 (m, 1H), 1.40-1.61 (m, 6H), 1.22-1.28 (m, 3H), 0.80-0.87 (m, 2H), 0.52-0.62 (m, 2H), 0.30 -0.37 (m, 2H).

Example 56: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -methyl- N- (tetrahydro- 2H -pyran-4-yl)pyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), N -methyltetrahydro- 2H -pyran-4-amine (93 mg, 0.81 mmol), 1-ethyl-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (54 mg, 0.40 mmol) were dissolved in dichloromethane (5 mL) , cooled to 0°C, added N , N -diisopropylethylamine (0.17 mL, 1.00 mmol), reacted at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 74 mg of white solid with a yield of 62% .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.91 – 7.94 (m, 1H), 7.57 – 7.63 (m, 1H), 7.41 – 7.45 (m, 1H), 7.12 (d, J = 8.2 Hz , 1H), 7.09 (s, 1H), 6.92 – 6.94 (m, 1H), 6.56 – 6.92 (m, 1H), 4.45 – 4.59 (m, 3H), 4.09 – 4.13 (m, 1H), 3.98 – 4.05 (m, 1H), 3.93 (d, J = 6.7 Hz, 2H), 3.69 – 3.79 (m, 1H), 3.66 (t, J = 10.5 Hz, 1H), 3.48 – 3.56 (m, 2H), 3.20 – 3.26 (m, 1H), 3.01 (s, 1.5H), 2.84 (s, 1.5H), 2.65 – 2.74 (m, 1H), 2.15 (s, 3H), 2.05 – 2.13 (m, 1H), 1.82 – 2.01 (m, 3H), 1.60 – 1.76 (m, 2H), 1.26 – 1.34 (m, 1H), 0.62 – 0.66 (m, 2H), 0.37 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 601.30 [M+H] ⁺ .

Example 57: Compound ( 2R )-1-Acetyl- N -((6-(azetidine-1-carbonyl)pyridin-2-yl)methyl)-4-(3-(cyclo) Propylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (102 mg, 0.20 mmol), azetidine (96 mg, 1.68 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride The salt (156 mg, 0.81 mmol) and N -hydroxy-7-azabenzotriazole (87 mg, 0.64 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C, and N , N - Diisopropylethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 18 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and concentrated The liquid was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 5 mg of pale yellow solid with a yield of 5%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.89 (t, J = 7.7 Hz, 1H), 7.75-7.80 (m, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 7.03 (t, J _FH = 74.9 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 4.57-4.61 (m, 2H), 4.35-4.45 (m, 3H), 4.03-4.07 (m, 3H), 3.90 (d, J = 6.8 Hz, 2H), 3.43-3.52 (m, 2H), 2.21-2.28 (m, 2H) , 2.03 (s, 3H), 1.91-1.99 (m, 2H), 1.28-1.31 (m, 1H), 0.53-0.59 (m, 2H), 0.30-0.34 (m, 2H).

MS (ESI, pos.ion) m/z: 543.20 [M+H] ⁺ .

Example 58: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( Pyrrolidine-1-carbonyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (94 mg, 0.18 mmol), tetrahydropyrrole (69 mg, 0.97 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 86 mg, 0.45 mmol) and N -hydroxy-7-azabenzotriazole (52 mg, 0.38 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C, added with N , N -diiso Propylethylamine (0.2 mL, 1.0 mmol), stirred at room temperature for 7 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was carried out Separation by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) gave 48 mg of white solid with a yield of 46%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.59 (t, J = 6.0 Hz, 1H), 7.84-7.90 (m, 1H), 7.48-7.55 (m, 2H), 7.12-7.14 (m, 1H), 7.06 (s, 1H), 7.03 (t, J _FH = 74.9 Hz, 1H), 6.88 (d, J = 9.5 Hz, 1H), 4.41-4.53 (m, 1H), 4.33-4.39 (m, 2H), 4.06-4.09 (m, 1H), 3.90 (d, J = 6.9 Hz, 2H), 3.51-3.59 (m, 2H), 3.39-3.49 (m, 4H), 2.58-2.63 (m , 1H), 2.03 (s, 3H), 1.89-1.94 (m, 1H), 1.80-1.83 (m, 4H), 1.23-1.26 (m, 1H), 0.54-0.59 (m, 2H), 0.33-0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 557.40 [M+H] ⁺ .

Example 59: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( Piperidine-1-carbonyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (103 mg, 0.20 mmol), piperidine (68 mg, 0.80 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.80 mmol) and N -hydroxy-7-azabenzotriazole (86 mg, 0.63 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C, and N , N -diisopropyl was added Ethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 20 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was washed with silica gel Column chromatography separation (eluent: dichloromethane/methanol (v/v) = 15/1) gave 75 mg of white solid, yield 64%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.59 (t, J = 5.7 Hz, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H) ), 7.32-7.38 (m, 1H), 7.10-7.14 (m, 1H), 7.06 (s, 1H), 7.03 (t, J _FH = 74.8 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H ), 4.33-4.43 (m, 3H), 4.05-4.09 (m, 1H), 3.90 (d, J = 6.8 Hz, 2H), 3.53-3.59 (m, 2H), 3.39-3.52 (m, 2H), 3.21-3.27 (m, 2H), 2.56-2.64 (m, 1H), 2.03 (s, 3H), 1.87-1.97 (m, 1H), 1.53-1.58 (m, 4H), 1.40-1.43 (m, 2H) ), 1.25-1.34 (m, 1H), 0.53-0.59 (m, 2H), 0.30-0.35 (m, 2H).

MS (ESI, pos.ion) m/z: 571.40 [M+H] ⁺ .

Example 60: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( Morpholine-4-carbonyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (103 mg, 0.20 mmol), morpholine (75 mg, 0.86 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (165 mg, 0.86 mmol) and N -hydroxy-7-azabenzotriazole (86 mg, 0.62 mmol) were dissolved in dichloromethane (6 mL), cooled to 0 °C, and N , N -diisopropyl was added Ethylethylamine (0.4 mL, 2.0 mmol), stirred at room temperature for 14 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was washed with silica gel Column chromatography separation (eluent: dichloromethane/methanol (v/v) = 15/1) gave 72 mg of a white solid with a yield of 61%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.60 (t, J = 5.8 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 7.03 (t, J _FH = 74.9 Hz, 1H), 6.89 (d , J = 9.1 Hz, 1H), 4.33-4.44 (m, 3H), 4.05-4.09 (m, 1H), 3.90 (d, J = 6.9 Hz, 2H), 3.60-3.66 (m, 4H), 3.50- 3.55 (m, 2H), 3.40-3.48 (m, 4H), 2.55-2.64 (m, 1H), 2.03 (s, 3H), 1.87-1.98 (m, 1H), 1.25-1.29 (m, 1H), 0.54-0.60 (m, 2H), 0.33-0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 573.25 [M+H] ⁺ .

Example 61: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( 4-Methylpiperazine-1-carbonyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (92 mg, 0.18 mmol), 1-methylpiperazine (89 mg, 0.89 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt The acid salt (163 mg, 0.85 mmol) and N -hydroxy-7-azabenzotriazole (89 mg, 0.65 mmol) were dissolved in dichloromethane (6 mL), and the solution was added dropwise at 0°C Add N , N -diisopropylethylamine (0.4 mL, 2.0 mmol), stir at room temperature for 14 h, add water (50 mL), extract with dichloromethane (5 mL × 3), and dry the organic phase with anhydrous sodium sulfate , the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 67 mg of pale yellow solid with a yield of 63%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.61 (t, J = 5.8 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 7.03 (t, J _FH = 74.8 Hz, 1H), 6.88 (d , J = 8.8 Hz, 1H), 4.42-4.53 (m, 1H), 4.33-4.39 (m, 2H), 4.05-4.09 (m, 1H), 3.90 (d, J = 6.8 Hz, 2H), 3.57- 3.69 (m, 2H), 3.37-3.51 (m, 4H), 2.58-2.64 (m, 1H), 2.40-2.451 (m, 2H), 2.25-2.40 (m, 2H), 2.24 (s, 3H), 2.03 (s, 3H), 1.89-1.99 (m, 1H), 1.25-1.34 (m, 1H), 0.54-0.60 (m, 2H), 0.31-0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 586.20 [M+H] ⁺ .

Example 62: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( 1-Methyl-1 H -pyrazol-5-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

Step 1: Synthesis of compound ((6-bromopyridin-2-yl)methyl)carbamate tert-butyl ester

The compound (6-bromopyridin-2-yl)methanamine (1.0 g, 5.4 mmol) was dissolved in a solution of dichloromethane (15 mL), and N , N -diisopropylethylamine (3.0 mL, 18.0 mmol) was added. ), di-tert-butyl dicarbonate (1.5 mL, 6.5 mmol) was added at 0 °C, stirred for 20 min, transferred to room temperature for 5 h, washed with water (50 mL), and extracted with dichloromethane (5 mL × 3 ), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 1.42 g of white solid, which was collected rate of 92%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.73 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.48 (br.s, 1H), 7.30 (d, J = 7.5 Hz, 1H), 4.19 (d, J = 6.0 Hz, 2H), 1.40 (s, 9H).

MS (ESI, pos.ion) m/z: 233.10 [M-55] ⁺ .

Step 2: Synthesis of compound ((6-(1-methyl- 1H -pyrazol-5-yl)pyridin-2-yl)methyl)carbamate tert-butyl ester

Compound ((6-bromopyridin-2-yl)methyl)carbamic acid tert-butyl ester (198 mg, 0.69 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) -1 H - pyrazole (153 mg, 0.74 mmol), sodium carbonate (232 mg, 2.19 mmol) and [1,1'-bis (diphenylphosphino The phosphino)ferrocene]palladium dichloride (29 mg, 0.04 mmol) was dissolved in anhydrous 1,4-dioxane (6 mL), the air was removed, nitrogen was passed through, and the reaction was carried out at 100 °C for 18 h, Water (50 mL) was added, extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 143 mg of pale yellow liquid with a yield of 72%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.86 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.45-7.48 (m, 2H), 7.24 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 4.30 (d, J = 6.0 Hz, 2H), 4.16 (s, 3H), 1.41 (s, 9H).

MS (ESI, pos.ion) m/z: 289.15 [M+H] ⁺ .

Step 3: Synthesis of compound (6-(1-methyl- 1H -pyrazol-5-yl)pyridin-2-yl)methanamine dihydrochloride

Compound ((6-(1-methyl- 1H -pyrazol-5-yl)pyridin-2-yl)methyl)carbamate (112 mg, 0.39 mmol) was dissolved in dichloromethane (2 mL) solution, 4 mol/L HCl in ethyl acetate solution (3 mL) was added, stirred at room temperature for 1 h, and the solvent was removed to obtain 71 mg of pale yellow solid with a yield of 97%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.48-8.63 (m, 2H), 7.96 (t, J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.47-7.50 (m, 2H), 6.84 (d, J = 1.7 Hz, 1H), 4.27 (d, J = 4.9 Hz, 2H), 4.19 (s, 3H).

MS (ESI, pos.ion) m/z: 189.30 [M+H-HCl] ⁺ .

Step 4: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-(1 Synthesis of -methyl- 1H -pyrazol-5-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (92 mg, 0.25 mmol), compound (6-(1-methyl- 1H -pyrazol-5-yl)pyridin-2-yl)methanamine dihydrochloride (811-3) (103 mg, 0.55 mmol), 1 -Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (150 mg, 0.78 mmol) and N -hydroxy-7-azabenzotriazole (71 mg, 0.52 mmol) It was dissolved in dichloromethane (6 mL), and N , N -diisopropylethylamine (0.4 mL, 2.0 mmol) was added dropwise to this solution at room temperature, stirred at room temperature for 6 h, and washed with water (50 mL) , extracted with dichloromethane (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/ 1), 67 mg of white solid was obtained, and the yield was 50%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.62 (s, 1H), 7.84-7.90 (m, 1H), 7.64-7.67 (m, 1H), 7.48 (s, 1H), 7.39 -7.40 (m, 1H), 7.10-7.16 (m, 1H), 7.06 (s, 2H), 7.04 (t, J _FH = 75.0 Hz, 1H), 6.88-6.91 (m, 1H), 6.78 (s, 1H), 4.38-4.53 (m, 3H), 4.15 (s, 3H), 4.05-4.10 (m, 1H), 3.90 (d, J = 4.7 Hz, 2H), 3.43-3.50 (m, 2H), 2.57 -2.67 (m, 1H), 2.04 (s, 3H), 1.88-1.96 (m, 1H), 1.23-1.26 (m, 1H), 0.50-0.61 (m, 2H), 0.28-0.38 (m, 2H) .

MS (ESI, pos.ion) m/z: 540.15 [M+H] ⁺ .

Example 63: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( 1-Methyl-1 H -pyrazol-4-yl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (91 mg, 0.25 mmol), compound (6-(1-methyl- 1H -pyrazol-4-yl)pyridin-2-yl)methanamine dihydrochloride (96 mg, 0.51 mmol), 1-ethyl-( 3-Dimethylaminopropyl)carbodiimide hydrochloride (153 mg, 0.79 mmol) and N -hydroxy-7-azabenzotriazole (71 mg, 0.52 mmol) in dichloromethane (6 mL), N , N -diisopropylethylamine (0.4 mL, 2.0 mmol) was added dropwise to this solution at room temperature, stirred at room temperature for 6 h, washed with water (50 mL), and washed with dichloromethane. Extraction (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain a white Solid 53 mg, yield 39%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.55 (br.s, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.68-7.72 (m, 1H), 7.48 -7.52 (m, 1H), 7.18-7.21 (m, 1H), 7.09-7.13 (m, 1H), 7.05-7.08 (m, 2H), 7.03 (t, J _FH = 74.9 Hz, 1H), 6.89 ( d, J = 8.3 Hz, 1H), 4.31-4.48 (m, 3H), 4.00-4.20 (m, 1H), 3.84-3.93 (m, 5H), 3.40-3.57 (m, 2H), 2.56-2.74 ( m, 1H), 2.04 (s, 3H), 1.91-1.96 (m, 1H), 1.22-1.29 (m, 1H), 0.49-0.65 (m, 2H), 0.27-0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 540.20 [M+H] ⁺ .

Example 64: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -methyl- N -phenylpyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.19 mmol), N -methylaniline (578 mg, 0.53 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (1925 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (40 mg, 0.29 mmol) were dissolved in dichloromethane (5 mL) and added dropwise to this solution at 0°C N , N -diisopropylethylamine (0.13 mL, 0.79 mmol), reacted at room temperature for 18 h, washed with water (15 mL), then extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate , the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 41 mg of white solid with a yield of 36%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.48 – 7.61 (m, 1H), 7.09 – 7.26 (m, 8H), 6.88 (s, 1H), 6.84 (d, J = 7.7 Hz, 1H) ), 6.60 (t, J _FH = 75.5 Hz, 1H), 4.430 – 4.55 (m, 1H), 4.31 – 4.45 (m, 2H), 3.87 – 3.96 (m, 1H), 3.86 (d, J = 6.7 Hz , 2H), 3.50 – 3.61 (m, 1H), 3.51 (s, 3H), 3.26 – 3.41 (m, 1H), 2.50 – 2.61 (m, 1H), 2.28 – 2.39 (m, 1H), 2.11 (s , 3H), 1.24 – 1.37 (m, 1H), 0.60 – 0.66 (m, 2H), 0.30 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 593.25 [M+H] ⁺ .

Example 65: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -methyl- N- (4-methylphenyl)pyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), N -methyl-4-methylaniline (62 mg, 0.51 mmol), 1-ethyl-(3-dimethylaminopropyl)carbanide Diimine hydrochloride (251 mg, 1.31 mmol) and N -hydroxy-7-azabenzotriazole (54 mg, 0.40 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 °C, N , N -diisopropylethylamine (183 mg, 1.42 mmol) was added, the reaction was carried out at room temperature for 22 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sodium sulfate After drying, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 84 mg of a white solid with a yield of 69%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.52 (br.s, 1H), 7.10 - 7.27 (m, 4H), 6.86 - 7.00 (m, 5H), 6.61 (t, J = 75.5 Hz , 1H), 4.43 - 4.50 (m, 3H), 3.87 - 3.94 (m, 3H), 3.53 - 3.65 (m, 1H), 3.45 (s, 3H), 3.25 - 3.42 (m, 1H), 2.50 - 2.64 (m, 1H), 2.26 - 2.40 (m, 1H), 2.26 (s, 3H), 2.13 (s, 3H), 1.26 - 1.35 (m, 1H), 0.60 - 0.72 (m, 2H), 0.29 - 0.45 (m, 2H).

MS (ESI, pos.ion) m/z: 607.40 [M+H] ⁺ .

Example 66: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (4- fluorophenyl) - N - methylpyridine Amides

Compound 6-(((2R)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino ) methyl)picolinic acid (102 mg, 0.20 mmol), 4-fluoro- N -methylaniline (50 mg, 0.40 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (192 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (40 mg, 0.29 mmol) were dissolved in dichloromethane (5 mL) and added to this solution at 0°C N ,N -diisopropylethylamine (0.17 mL, 1.00 mmol) was added dropwise to it, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous It was dried over sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 49 mg of white solid with a yield of 39%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.55 – 7.68 (m, 1H), 7.28 – 7.43 (m, 1H), 7.04 – 7.17 (m, 4H), 6.84 – 6.98 (m, 4H) , 6.62 (t, J _FH = 75.6 Hz, 1H), 4.40 – 4.51 (m, 3H), 3.86 – 3.98 (m, 1H), 3.88 (d, J = 5.8 Hz, 2H), 3.49 – 3.59 (m, 1H), 3.50 (s, 3H), 3.28 – 3.43 (m, 1H), 2.49 – 2.60 (m, 1H), 2.36 – 2.48 (m, 1H), 2.15 (s, 3H), 1.26 – 1.36 (m, 1H), 0.66 – 0.70 (m, 2H), 0.33 – 0.342 (m, 2H).

MS (ESI, pos.ion) m/z: 611.30 [M+H] ⁺ .

Example 67: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (2,4-difluorophenyl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (86 mg, 0.17 mmol), 2,4-difluoro- N -methylaniline (41 mg, 0.29 mmol), 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (173 mg, 0.90 mmol) and N -hydroxy-7-azabenzotriazole (48 mg, 0.35 mmol) were dissolved in dichloromethane (5 mL) at 0°C N , N -diisopropylethylamine (0.15 mL, 0.91 mmol) was added dropwise to this solution, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), and then extracted with dichloromethane (5 mL × 3), The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 33 mg of white solid, yield 30% .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.60 – 7.66 (m, 1H), 7.44 – 7.52 (m, 1H), 7.18 (d, J = 7.5Hz, 1H), 7.06 – 7.13 (m , 3H), 6.89 (s, 1H), 6.84 (d, J = 8.0Hz, 1H), 6.69 – 6.76 (m, 1H), 6.60 (t, J _FH = 75.6 Hz, 1H), 4.45 – 4.58 (m , 1H), 4.25 – 4.38 (m, 2H), 3.88 – 3.98 (m, 1H), 3.86 (d, J = 6.6 Hz, 2H), 3.56 (d, J = 10.4Hz, 1H), 3.42 (s, 3H), 3.25 – 3.41 (m, 1H), 2.48 – 2.62 (m, 1H), 2.34 – 2.44 (m, 1H), 2.13 (s, 3H), 1.24 – 1.36 (m, 1H), 0.62 – 0.66 ( m, 2H), 0.32 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 629.30 [M+H] ⁺ .

Example 68: Compound 6-((( 2R )-1-acetyl-4-(3-((2-cyclopropylpropan-2-yl)oxy)-4-(difluoromethoxy) ) phenyl) pyrrolidine-2-acyl-amino) methyl) - N - (4- fluorophenyl) - N - methylpyridine Amides

Step 1: Compound ( R )-1-Acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole- Synthesis of 2-Carboxylic Acid

The compound ( R )-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2- Methyl carboxylate (1.8 g, 0.56 mmol) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and water (8 mL), lithium hydroxide monohydrate (964 mg, 23 mmol) was added, and the reaction was stopped after 2 h at 50 °C , dilute hydrochloric acid was added to adjust the pH of the solution to 1, extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 1.6 g of a pale yellow solid with a yield of 94%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.49 – 7.51 (m, 2H), 7.38 – 7.42 (m, 2H), 7.29 – 7.32 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 7.08 – 7.11 (m, 1H), 6.78 (t, J _FH = 74.8 Hz, 1H), 6.31 – 6.34 (m, 1H), 5.39 – 5.42 (m, 0.3H), 5.22 – 5.25 ( m, 0.7H), 5.22 (s, 2H), 4.75 – 4.82 (m, 2H), 2.22 (s, 2H), 2.07 (s, 1H).

MS (ESI, pos.ion) m/z: 404.05 [M+H] ⁺ .

Step 2: Compound ( R )-6-((1-Acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1 H - pyrrole-2-acyl-amino) methyl) - N - (4- fluorophenyl) - N - synthesis of Amides methylpyridine

The compound ( R )-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2- carboxylic acid (200 mg, 0.50 mmol), 6- ( aminomethyl) - N - (4- fluorophenyl) - N - methyl acyl pyridine dihydrochloride (889-1) (181 mg, 0.54 mmol ), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (476 mg, 2.48 mmol) and N -hydroxy-7-azabenzotriazole (136 mg, 1.00 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, N , N -diisopropylethylamine (0.6 mL, 4.0 mmol) was added, the reaction was carried out at room temperature for 12 h, and washed with water (20 mL). ) was stirred, the organic phase was separated, the organic phase was dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 301 mg of white solid, Yield 94%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.37 – 7.47 (m, 6H), 7.16 – 7.22 (m, 2H), 7.00 – 7.12 (m, 4H), 6.86 – 6.98 (m, 3H) , 6.60 (t, J _FH = 74.9 Hz, 1H), 6.17 – 6.20 (m, 1H), 5.30 – 5.36 (m, 0.7H), 5.19 – 5.23 (m, 0.3H), 5.17 (s, 2H), 4.61 – 4.78 (m, 2H), 4.29 – 4.49 (m, 2H), 3.50 (s, 3H), 2.22 (s, 2H), 2.07 (s, 1H).

MS (ESI, pos.ion) m/z: 645.10 [M+H] ⁺ .

Step 3: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carbamoylamino)methyl) - Synthesis of N- (4-fluorophenyl) -N-picolinamide

Compound (R) -6 - ((1- acetyl-4- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -2,5-dihydro -1 H - acyl pyrrole-2-ylamino) methyl) - N - (4- fluorophenyl) - N - Amides methylpyridine (301 mg, 0.47mmol) was dissolved in methanol (10 mL), was added Pd / C (33 mg, 10%), passed hydrogen into the reaction at room temperature for 8 h, filtered to remove the catalyst, concentrated the filtrate, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 25/1) to obtain White solid 227 mg, yield 87%.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.54 – 7.58 (m, 1H), 7.17 – 7.24 (m, 2H), 7.00 – 7.14 (m, 4H), 6.92 – 6.98 (m, 2H) , 6.78 (d, J = 8.0 Hz, 1H), 6.55 (t, J _FH = 74.4 Hz, 1H), 4.55 – 4.63 (m, 0.4H), 4.43 – 4.53 (m, 2H), 4.28 – 4.33 (m , 0.6H), 4.13 – 4.16 (m, 0.4H), 3.92 – 3.96 (m, 0.7H), 3.61 – 3.65 (m, 1H), 3.52 – 3.54 (m, 3H), 3.29 – 3.40 (m, 1H) ), 2.81 – 2.86 (m, 0.3H), 2.55 – 2.61 (m, 0.7H), 2.32 – 2.39 (m, 1H), 2.17 (s, 2H), 2.08 (s, 1H).

MS (ESI, pos.ion) m/z: 557.15 [M+H] ⁺ .

Step 4: Compound 6-((( 2R )-1-acetyl-4-(3-((2-cyclopropylpropan-2-yl)oxy)-4-(difluoromethoxy) phenyl) pyrrolidine-2-acyl-amino) methyl) - N - (4- fluorophenyl) - N - synthesis of Amides methylpyridine

The 6 - (((2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-hydroxyphenyl) pyrrolidine-2-acyl-amino) methyl) - N - (4-Fluorophenyl) -N -picolinamide (112 mg, 0.20 mmol), 1-cyclopropyl-1-methylethanol (60 mg, 0.60 mmol), triphenylphosphine (101 mg, 0.50 mmol) was dissolved in dry tetrahydrofuran (10 mL) solution, azodimethylamide (100 mg, 0.58 mmol) was slowly added under ice bath conditions, reacted at 30 °C for 12 h, added water (10 mL), and washed with ethyl acetate. (5 mL × 3) extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 56 mg of white solid , the yield is 43%.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.57 – 7.65 (m, 1H), 7.31 – 7.38 (m, 1H), 7.17 – 7.20 (m, 1H), 7.12 (d, J = 8.2 Hz , 1H), 7.05 – 7.09 (m, 3H), 7.00 (d, J = 8.2 Hz, 1H), 6.90 – 6.96 (m, 2H), 6.58 (t, J _FH = 75.7 Hz, 1H), 4.50 – 4.54 (m, 1H), 4.36 – 4.44 (m, 2H), 3.95 – 3.98 (m, 1H), 3.57 (t, J = 10.7 Hz, 1H), 3.51 (s, 3H), 3.31 – 3.39 (m, 1H) ), 3.54 – 3.59 (m, 1H), 3.38 – 3.46 (m, 1H), 2.16 (s, 3H), 1.26 (s, 6H), 1.16 – 1.23 (m, 1H), 0.48 – 0.51 (m, 2H) ), 0.38 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 661.15 [M+Na] ⁺ .

Example 69: Compound 6 - (((2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-2 methyl acyl amino) methyl) - N - (4- fluorophenyl) - N - methylpyridine Amides

Step 1: Compound (2 R) -1- tert-butyl 2-methyl-4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) -pyrrolidine-l, Synthesis of Dicarboxylates

Compound ( 2R )-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-1,2-dicarboxylate (510 mg, 1.32 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled to 0 °C, 60% sodium hydride (71 mg, 1.78 mmol) was added, the reaction was carried out at room temperature for 30 min, and iodomethane- d ₃ (382 mmol) was added to the ice bath mg, 2.64 mmol), the reaction was stopped after 7 h at room temperature, ice water (10 mL) was slowly added, extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and concentrated under reduced pressure to carry out Silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1) gave 127 mg of a colorless liquid with a yield of 24%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.13 (d, J = 8.1 Hz, 1H), 6.81 – 6.85 (m, 2H), 6.54 (t, J _FH = 75.2 Hz, 1H), 4.34 – 4.44 (m, 1H), 4.06 – 4.10 (m, 0.6H), 3.95 – 3.99 (m, 0.4H), 3.79 (d, J = 6.9 Hz, 1H), 3.43 – 3.49 (m, 1H), 3.33 – 3.39 (m, 1H), 2.64 – 2.72 (m, 1H), 2.01 – 2.12 (m, 1H), 1.46 – 1.49 (m, 9H).

MS (ESI, pos.ion) m/z: 349.20 [M-55] ⁺ .

Step 2: Compound (2 R) -4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-2-carboxylic acid methyl ester hydrochloride

Compound (2 R) -1- tert-butyl 2-methyl-4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-1,2-dicarboximide The acid ester (123 mg, 0.30 mmol) was dissolved in dichloromethane (6 mL) solution, 4 mol/L HCl in ethyl acetate solution (5 mL) was added, the reaction was carried out at room temperature for 1 h, and the solvent was removed to obtain a colorless liquid 102 mg, 98% yield.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.14 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.92 (dd, J = 8.2, 1.9 Hz , 1H), 6.71 (t, J _FH = 75.4 Hz, 1H), 4.61 – 4.65 (m, 1H), 3.90 (s, 3H), 3.80 – 3.84 (m, 1H), 3.68 – 3.75 (m, 1H) , 3.36 – 3.41 (m, 1H), 2.84 – 2.90 (m, 1H), 2.22 – 2.31 (m, 1H).

MS (ESI, pos.ion) m/z: 305.15 [M+H-HCl] ⁺ .

Step 3: Compound (2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-2-carboxylate synthesis

Compound (2 R) -4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-2-carboxylic acid methyl ester hydrochloride (100 mg, 0.29 mmol ) was dissolved in dichloromethane (3 mL), cooled to 0 °C, added N , N -diisopropylethylamine (0.15 mL, 0.91 mmol), acetyl chloride (69 mg, 0.88 mmol), room temperature The reaction was stopped after 4 h, water (15 mL) was added, and dichloromethane was extracted (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether/ Ethyl acetate (v/v) = 1/1) to obtain a pale yellow liquid 93 mg with a yield of 91%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14 (d, J = 7.9 Hz, 1H), 6.85 (s, 1H), 6.79 – 6.83 (m, 1H), 6.55 (t, J _FH = 75.1 Hz, 1H), 4.49 – 4.53 (m, 1H), 3.95 – 3.99 (m, 1H), 3.79 (s, 3H), 3.65 (t, J = 10.4 Hz, 1H), 3.41 – 3.48 (m, 1H) ), 2.66 – 2.73 (m, 1H), 2.14 (s, 3H), 2.04 – 2.10 (m, 1H).

MS (ESI, pos.ion) m/z: 347.10 [M+H] ⁺ .

Step 4: Compound (2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-2-carboxylic acid

Compound (2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-2-carboxylate (92 mg , 0.27 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and water (3 mL), lithium hydroxide monohydrate (56 mg, 1.34 mmol) was added, the reaction was stopped at 50 °C for 30 min, and diluted hydrochloric acid was added to adjust the pH of the solution = 1, extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 87 mg of light yellow liquid, the yield was 98%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.12 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 8.3, 2.0 Hz , 1H), 6.69 (t, J _FH = 75.5 Hz, 1H), 4.44 – 4.49 (m, 1H), 4.09 – 4.15 (m, 1H), 3.49 – 3.56 (m, 1H), 3.58 – 3.65 (m, 1H), 2.73 – 2.80 (m, 1H), 2.14 (s, 3H), 2.02 – 2.10 (m, 1H).

MS (ESI, pos.ion) m/z: 333.10 [M+H] ⁺ .

Step 5: Compound 6 - (((2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-2- acyl amino) methyl) - N - (4- fluorophenyl) - N - acyl amine-methylpyridine

Compound (2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-2-carboxylic acid (45 mg, 0.14 mmol), 6- (aminomethyl) - N - (4- fluorophenyl) - N - methyl acyl pyridine dihydrochloride (889-1) (61 mg, 0.18 mmol), 1- ethyl - (3-Dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.69 mmol) and N -hydroxy-7-azabenzotriazole (36 mg, 0.26 mmol) in dichloro In methane (10 mL), after cooling to 0 °C, N , N -diisopropylethylamine (0.16 mL, 0.97 mmol) was added, the reaction was carried out at room temperature for 11 h, water (20 mL) was added, stirred for 5 min, and dichloromethane was added. Methane extraction (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) , 37 mg of white solid was obtained, and the yield was 47%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.52 – 7.67 (m, 1H), 7.34 (br.s, 1H), 7.00 – 7.20 (m, 5H), 6.83 – 6.99 (m, 4H) , 6.55 (t, J _FH = 75.2 Hz, 1H), 4.47 – 4.57 (m, 1H), 4.32 – 4.47 (m, 2H), 3.95 – 3.99 (m, 1H), 3.60 (t, J = 10.5 Hz, 1H), 3.49 (s, 3H), 3.30 – 3.45 (m, 1H), 2.52 – 2.62 (m, 1H), 2.39 – 2.48 (m, 1H), 2.15 (s, 3H).

MS (ESI, pos.ion) m/z: 574.35 [M+H] ⁺ .

Example 70: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethyl oxy) phenyl) pyrrolidine-2-acyl-amino) methyl) - N - (4- fluorophenyl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)benzene yl)pyrrolidine-2-carbamoylamino)methyl)picolinic acid (90 mg, 0.18 mmol), 4-fluoro- N -methylbenzene (44 mg, 0.35 mmol), 1-ethyl-(3-di- Methylaminopropyl)carbodiimide hydrochloride (172 mg, 0.9 mmol) and N -hydroxy-7-azabenzotriazole (49 mg, 0.36 mmol) were dissolved in dichloromethane (5 mL) ), cooled to 0 °C, added N , N -diisopropylethylamine (0.21 mL, 1.3 mmol), reacted at room temperature for 18 h, added water (15 mL), and extracted with dichloromethane (5 mL × 3) , the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, concentrated, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 46 mg of white solid, yield 43 %.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.63 – 7.77 (m, 1H), 7.34 – 7.48 (m, 1H), 7.08 – 7.28 (m, 5H), 6.90 – 7.02 (m, 3H) ), 6.74 (t, J _FH = 75.2 Hz, 1H), 4.38 – 4.53 (m, 2H), 4.21 – 4.32 (m, 1H), 4.06 – 4.15 (m, 1H), 3.62 – 3.67 (m, 1H) , 3.37 – 3.54 (m, 1H), 3.46 (s, 3H), 2.61 – 2.75 (m, 1H), 2.14 (s, 3H), 1.99 – 2.13 (m, 1H), 1.26 – 1.40 (m, 1H) , 0.60 – 0.68 (m, 2H), 0.32 – 0.44 (m, 2H).

MS (ESI, pos.ion) m/z: 613.80 [M+H] ⁺ .

Example 71: Compound 6-((( 2R )-1-Acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl) - N- (4-Fluorophenyl) -N -picolinamide

The compound 6-((( 2R )-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl)picolinic acid ( 80 mg, 0.16 mmol), 4-fluoro- N -methylaniline (26 mg, 0.21 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg , 0.79 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL), to this solution was added dropwise N , N - Diisopropylethylamine (0.13 mL, 0.79 mmol) was reacted at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed, The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 81 mg of white solid with a yield of 83%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.56 – 7.65 (m, 1H), 7.31 – 7.38 (m, 1H), 7.17 – 7.25 (m, 3H), 7.05 – 7.14 (m, 3H) , 6.91 – 6.98 (m, 2H), 6.56 (t, J _FH = 73.6 Hz, 1H), 6.53 (t, J _FH = 73.6 Hz, 1H), 4.48 – 4.60 (m, 1H), 4.34 – 4.48 (m , 2H), 3.97 – 4.01 (m, 1H), 3.58 (t, J = 10.6 Hz, 1H), 3.50 (s, 3H), 3.30 – 3.45 (m, 1H), 2.55 – 2.60 (m, 1H), 2.38 – 2.40 (m, 1H), 2.16 (s, 3H).

MS (ESI, pos.ion) m/z: 607.20 [M+H] ⁺ .

Example 72: Compound 6-((( 2R )-1-Acetyl-4-(2,2-difluorobenzo[ d ][1,3]dioxocen-5-yl)pyrrolidine- 2-acyl-amino) methyl) - N - (4- fluorophenyl) - N - methylpyridine Amides

Step 1: Compound (R) -1- tert-butyl 2-methyl-4- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -1 H - pyrrole - Synthesis of 1,2( 2H , 5H)-dicarboxylate

( R )-1-tert-butyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1 H -pyrrole-1,2( 2H , 5H )-dicarboxylate (320 mg, 0.9 mmol), 5-bromo-2,2-difluorobenzo[ d ][1,3]dioxin (475 mg, 2.0 mmol), potassium phosphate (1.1 g, 5.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (26 mg) were mixed in dry 1, 4-dioxane (8 mL) solution was reacted at 100 °C for 12 h under nitrogen protection, cooled to room temperature, concentrated under reduced pressure, the residue was added with water (20 mL), and extracted with ethyl acetate (15 mL × 3) , the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1) to obtain a light brown liquid 324 mg, yield 93%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14 (s, 1H), 7.05 – 7.11 (m, 2H), 6.05 – 6.07 (m, 0.4H), 6.00 – 6.02 (m, 0.6H) , 5.20 – 5.23 (m, 0.4H), 5.12 – 5.15 (m, 0.6H), 4.50 – 4.67 (m, 2H), 3.79 (s, 1H), 3.78 (s, 2H), 1.54 (s, 3.4H) ), 1.48 (s, 5.6H).

MS (ESI, pos.ion) m/z: 406.00 [M+Na] ⁺ .

Step 2: Compound ( 2R )-1-tert-butyl 2-methyl 4-(2,2-difluorobenzo[ d ][1,3]dioxocen-5-yl)pyrrolidine-1, Synthesis of 2-dicarboxylate

The compound (R) -1- tert-butyl 2-methyl-4- (2,2-difluorobenzo [d] [1,3] dioxol-5-yl) -1 H - pyrrole-1, 2( 2H , 5H )-dicarboxylate (320 mg, 0.83 mmol) was dissolved in methanol (8 mL), Pd/C (32 mg) was added, hydrogen was passed through it and reacted at room temperature for 5 h, the catalyst was removed by filtration, and the filtrate was Concentration gave 306 mg of a colorless liquid with a yield of 95%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.95 – 7.03 (m, 3H), 4.33 – 4.43 (m, 1H), 4.04 – 4.10 (m, 0.6H), 3.94 – 4.00 (m, 0.4 H), 3.79 (s, 1H), 3.78 (s, 2H), 3.42 (t, J = 10.1 Hz, 1H), 3.32 – 3.41 (m, 1H), 2.64 – 2.71 (m, 1H), 2.00 – 2.09 (m, 1H), 1.49 (s, 3H), 1.45 (s, 6H).

MS (ESI, pos.ion) m/z: 408.10 [M+Na] ⁺ .

Step 3: Synthesis of Compound (2R )-4-(2,2-difluorobenzo[ d ][1,3]dioxoc-5-yl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

The compound (2 R )-1-tert-butyl 2-methyl 4-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)pyrrolidine-1,2- Dicarboxylate (300 mg, 0.78 mmol) was dissolved in dichloromethane (5 mL) solution, 4 mol/L HCl in ethyl acetate solution (5 mL) was added, the reaction was carried out at room temperature for 1 h, and the solvent was removed to obtain a white Solid 248 mg, 99% yield.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.29 (s, 1H), 7.20 – 7.22 (m, 1H), 7.16 – 7.18 (m, 1H), 4.61 – 4.66 (m, 1H), 3.90 (s, 3H), 3.69 – 3.85 (m, 2H), 3.34 – 3.38 (m, 1H), 2.84 – 2.91 (m, 1H), 2.20 – 2.28 (m, 1H).

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

Step 4: Compound ( 2R )-1-Acetyl-4-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)pyrrolidine-2-carboxylic acid methyl Synthesis of Esters

The compound ( 2R )-4-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)pyrrolidine-2-carboxylate methyl ester hydrochloride (245 mg, 0.76 mmol) was dissolved in dichloromethane (6 mL), cooled to 0 °C, N , N -diisopropylethylamine (0.63 mL, 3.8 mmol) and acetyl chloride (181 mg, 2.3 mmol) were added, and the After 3 h of warm stirring, water (15 mL) was added, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) to obtain 221 mg of pale yellow liquid with a yield of 88%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.95 – 7.05 (m, 3H), 6.55 (t, J _FH = 75.1 Hz, 1H), 4.49 – 4.53 (m, 1H), 3.95 – 3.99 ( m, 1H), 3.79 (s, 3H), 3.62 (t, J = 10.4 Hz, 1H), 3.42 – 3.51 (m, 1H), 2.66 – 2.73 (m, 1H), 2.13 (s, 3H), 2.00 – 2.10 (m, 1H).

MS (ESI, pos.ion) m/z: 328.20 [M+H] ⁺ .

Step 5: Compound ( 2R )-1-Acetyl-4-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)pyrrolidine-2-carboxylic acid synthesis

The compound ( 2R )-1-acetyl-4-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)pyrrolidine-2-carboxylate methyl ester ( 220 mg, 0.67 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and water (3 mL), and then lithium hydroxide monohydrate (56 mg, 1.34 mmol) was added, the reaction was stopped at 50 °C for 30 min, and diluted hydrochloric acid was added. The pH of the solution was adjusted to 1, and then extracted with ethyl acetate (10 mL × 3). The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain 207 mg of a light yellow liquid with a yield of 98%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.26 (s, 1H), 7.14 – 7.19 (m, 2H), 4.44 – 4.48 (m, 1H), 4.09 – 4.15 (m, 1H), 3.56 – 3.63 (m, 2H), 2.74 – 2.80 (m, 1H), 2.14 (s, 3H), 2.00 – 2.08 (m, 1H).

MS (ESI, pos.ion) m/z: 314.20 [M+H] ⁺ .

Step 6: Compound 6-((( 2R )-1-Acetyl-4-(2,2-difluorobenzo[ d ][1,3]dioxocen-5-yl)pyrrolidine-2 - a XI) methyl) - N - (4- fluorophenyl) - N - acyl amine-methylpyridine

The compound ( 2R )-1-acetyl-4-(2,2-difluorobenzo[ d ][1,3]dioxoc-5-yl)pyrrolidine-2-carboxylic acid (60 mg , 0.19 mmol), 6- (aminomethyl) - N - (4- fluorophenyl) - N - methyl acyl pyridine dihydrochloride (889-1) (77 mg, 0.23 mmol), 1- ethyl Alkyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (182 mg, 0.95 mmol) and N -hydroxy-7-azabenzotriazole (52 mg, 0.38 mmol) were dissolved in In dichloromethane (6 mL), cooled to 0 °C, N , N -diisopropylethylamine (0.22 mL, 1.3 mmol) was added, the reaction was carried out at room temperature for 11 h, water (20 mL) was added, stirred for 5 min, and separated. The organic phase was dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 64 mg of white solid, which was then subjected to high-efficiency Preparative separation by liquid chromatography gave 39 mg of white solid with a yield of 36%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.50 – 7.63 (m, 2H), 7.19 – 7.28 (m, 1H), 7.13 – 6.92 (m, 7H), 4.53 – 4.57 (m, 1H) , 4.34 – 4.47 (m, 2H), 3.93 – 3.98 (m, 1H), 3.57 (t, J = 10.6 Hz, 1H), 3.50 (s, 3H), 3.35 – 3.49 (m, 1H), 2.55 – 2.62 (m, 1H), 2.33 – 2.47 (m, 1H), 2.13 (s, 3H).

MS (ESI, pos.ion) m/z: 555.85 [M+H] ⁺ .

Example 73: Compound 6-((( 2R )-1-Acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2 - (methanesulfonamide acyl) phenyl) pyrrolidine-2-acyl-amino) methyl) - N - (4- fluorophenyl) - N - methylpyridine Amides

Step 1: Compound ( R )-1-tert-butyl 2-methyl 4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methyl) sulfonic yl) phenyl) -1 H - pyrrole -1,2 (2 H, 5 H) - synthesis of esters of dicarboxylic acids

The compound (R) -1- tert-butyl 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H -pyrrole-1,2( 2H , 5H )-dicarboxylate (300 mg, 0.85 mmol), N- (5-bromo-2-(difluoromethoxy)-4-(methylsulfonyl) ) phenyl) - N - (cyclopropylmethyl) hydroxylamine (334 mg, 0.86mmol), potassium phosphate (721 mg, 3.40mmol) and [1,1'-bis (diphenylphosphino) ferrocene ] Palladium dichloride (24 mg) was mixed in dry 1,4-dioxane (8 mL) solution, reacted at 100 °C for 3 h under nitrogen protection, cooled to room temperature, concentrated under reduced pressure, and the residue was added with water (20 mL), extracted with ethyl acetate (15 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 5/1) to obtain 381 mg of pale yellow liquid with a yield of 84%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.14 – 7.15 (m, 1H), 6.53 (t, J _FH = 73.3 Hz, 1H), 6.49 (s, 1H), 6.19 – 6.21 (m, 0.7H), 6.10 – 6.12 (m, 0.3H), 5.19 – 5.23 (m, 0.3H), 5.14 – 5.17 (m, 0.7H), 4.58 – 4.67 (m, 2H), 3.79 (s, 3H), 3.03 – 3.05 (m, 3H), 2.95 – 2.98 (m, 2H), 1.45 – 1.53 (m, 9H), 1.08 – 1.16 (m, 1H), 0.60 – 0.65 (m, 2H), 0.26 – 0.30 (m , 2H).

MS (ESI, pos.ion) m/z: 533.90 [M+H] ⁺ .

Step 2: Compound ( 2R )-1-tert-butyl 2-methyl 4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-( Synthesis of Methylsulfonyl)phenyl)pyrrolidine-1,2-dicarboxylate

The compound ( R )-1-tert-butyl-2-methyl 4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methanesulfonyl) yl) phenyl) -1 H - pyrrole -1,2 (2 H, 5 H) - dicarboxylate (380 mg, 0.71mmol) was dissolved in methanol (8mL), was added Pd / C (32 mg, 10 % ), passed into hydrogen and reacted at room temperature for 24 h, filtered to remove the catalyst, the filtrate was concentrated, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain a colorless liquid 226 mg, 59% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.01 (s, 1H), 6.65 (s, 1H), 6.48 (t, J _FH = 73.6 Hz, 1H), 4.33 – 4.42 (m, 2H) , 3.92 – 4.04 (m, 1H), 3.80 (s, 1H), 3.64 – 3.73 (m, 1H), 3.43 – 3.50 (m, 1H), 3.24 (s, 3H), 2.96 – 3.00 (m, 2H) , 2.67 – 2.75 (m, 1H), 1.96 – 2.04 (m, 1H), 1.48 (s, 3.4H), 1.45 (s, 5.6H), 1.07 – 1.14 (m, 1H), 0.60 – 0.64 (m, 2H), 0.27 – 0.31 (m, 2H).

MS (ESI, pos.ion) m/z: 535.10 [M+H] ⁺ .

Step 3: Compound ( 2R )-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl)phenyl)pyrrole Synthesis of Alkane-2-Carboxylic Acid Methyl Hydrochloride

The compound (2 R )-1-tert-butyl 2-methyl 4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methanesulfonic acid) Acyl)phenyl)pyrrolidine-1,2-dicarboxylate (221 mg, 0.41 mmol) was dissolved in dichloromethane (3 mL) solution, 4 mol/L HCl in ethyl acetate solution (6 mL) was added ), reacted at room temperature for 1 h, and removed the solvent to obtain 191 mg of white solid with a yield of 98%.

¹ H NMR (600 MHz, CD ₃ OD) δ (ppm): 7.30 (s, 1H), 7.29 (s, 1H), 6.99 (t, J _FH = 72.8 Hz, 1H), 4.65 – 4.68 (m, 1H) ), 4.05 – 4.08 (m, 1H), 3.92 (s, 3H), 3.82 – 3.86 (m, 1H), 3.46 (s, 3H), 3.37 – 3.41 (m, 1H), 3.21 (d, J = 7.0 Hz, 2H), 2.84 – 2.88 (m, 1H), 2.29 – 2.35 (m, 1H), 1.15 – 1.20 (m, 1H), 0.64 – 0.67 (m, 2H), 0.35 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 435.05 [M+H-HCl] ⁺ .

Step 4: Compound ( 2R )-1-Acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl Synthesis of methyl)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl)phenyl)pyrrolidine- Methyl 2-carboxylate hydrochloride (190 mg, 0.41 mmol) was dissolved in dichloromethane (6 mL), N , N -diisopropylethylamine (0.41 mL, 2.5 mmol) and Acetyl chloride (96 mg, 1.22 mmol), stirred at room temperature for 40 min, then stopped, added water (15 mL), extracted with dichloromethane (15 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and silica gel Column chromatography separation (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) gave 162 mg of a colorless liquid with a yield of 84%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.00 (s, 1H), 6.56 (s, 1H), 6.50 (t, J _FH = 73.4 Hz, 1H), 4.48 – 4.52 (m, 1H) , 4.33 – 4.40 (m, 1H), 3.98 – 4.02 (m, 1H), 3.80 (s, 3H), 3.74 – 3.80 (m, 1H), 3.57 – 3.62 (m, 1H), 3.26 (s, 3H) , 3.37 – 3.41 (m, 1H), 2.98 – 3.02 (m, 2H), 2.64 – 2.71 (m, 1H), 2.12 (s, 3H), 2.01 – 2.09 (m, 1H), 1.07 – 1.16 (m, 1H), 0.61 – 0.66 (m, 2H), 0.29 – 0.33 (m, 2H).

MS (ESI, pos.ion) m/z: 477.90 [M+H] ⁺ .

Step 5: Compound ( 2R )-1-Acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl Synthesis of yl)phenyl)pyrrolidine-2-carboxylic acid

The compound ( 2R )-1-acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl) Phenyl)pyrrolidine-2-carboxylate methyl ester (153 mg, 0.32 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL) and water (4 mL), and lithium hydroxide monohydrate (67 mg, 1.60 mmol) was added , the reaction was stopped after 1 h at 50 °C, diluted hydrochloric acid was added to adjust the pH of the solution to 1, extracted with ethyl acetate (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 133 mg of a light brown solid with a yield of 89 %.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.10 (s, 1H), 6.79 (t, J _FH = 73.8 Hz, 1H), 7.14 – 7.19 (m, 2H), 6.77 (s, 1H) ), 4.45 – 4.49 (m, 1H), 4.05 – 4.13 (m, 1H), 3.80 – 3.89 (m, 1H), 3.61 – 3.73 (m, 1H), 3.35 (s, 3H), 3.05 – 3.08 (m , 2H), 2.71 – 2.78 (m, 1H), 2.12 (s, 2H), 2.01 (s, 1H), 2.01 – 2.10 (m, 1H), 1.10 – 1.14 (m, 1H), 0.55 – 0.60 (m , 2H), 0.28 – 0.31 (m, 2H).

MS (ESI, pos.ion) m/z: 463.90 [M+H] ⁺ .

Step 6: Compound 6-((( 2R )-1-Acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2- (acyl methanesulfonamide) phenyl) pyrrolidine-2-acyl-amino) methyl) - N - (4- fluorophenyl) - N - acyl amine-methylpyridine

The compound ( 2R )-1-acetyl-4-(5-((cyclopropylmethyl)(hydroxy)amino)-4-(difluoromethoxy)-2-(methylsulfonyl) phenyl) pyrrolidine-2-carboxylic acid (60 mg, 0.13 mmol), 6- ( aminomethyl) - N - (4- fluorophenyl) - N - methyl acyl pyridine dihydrochloride (51 mg , 0.15 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (124 mg, 0.65 mmol) and N -hydroxy-7-azabenzotriazole ( 36 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, N , N -diisopropylethylamine (0.15 mL, 0.91 mmol) was added, the reaction was carried out at room temperature for 12 h, and water ( 20 mL) was stirred for 5 min, the organic phase was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1), 53 mg of white solid was obtained in 58% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.61 (br.s, 1H), 7.33 – 7.46 (m, 1H), 7.16 – 7.24 (m, 1H), 6.98 – 7.09 (m, 5H) , 6.68 (s, 1H), 6.50 (t, J _FH = 74.0 Hz, 1H), 4.35 – 4.83 (m, 4H), 3.97 – 4.07 (m, 1H), 3.63 – 3.74 (m, 1H), 3.50 ( s, 3H), 3.65 (s, 3H), 2.93 – 3.04 (m, 2H), 2.48 – 2.59 (m, 1H), 2.36 – 2.48 (m, 1H), 2.13(s, 3H), 1.05 – 1.14 ( m, 1H), 0.56 – 0.64 (m, 2H), 0.25 – 0.32 (m, 2H).

MS (ESI, pos.ion) m/z: 704.40 [M+H] ⁺ .

Example 74: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxyamino)methyl) -N -methyl- N- (4-methoxyphenyl)pyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), N -methyl-4-methoxyaniline (68 mg, 0.50 mmol), 1-ethyl-(3-dimethylaminopropyl) carbon Diimide hydrochloride (251 mg, 1.31 mmol) and N -hydroxy-7-azabenzotriazole (54 mg, 0.40 mmol) were dissolved in dichloromethane (5 mL) and cooled to 0°C , N , N -diisopropylethylamine (180 mg, 1.39 mmol) was added, the reaction was carried out at room temperature for 22 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sulfuric acid The solution was dried over sodium, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 73 mg of a gray solid with a yield of 59%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.63 (br.s, 1H), 7.19 - 7.31 (m, 2H), 7.05 - 7.12 (m, 3H), 6.77 - 6.92 (m, 4H) , 6.62 (t, J = 75.5 Hz, 1H), 4.38 - 4.62 (m, 3H), 3.81 - 3.99 (m, 1H), 3.89 (s, 2H), 3.64 - 3.80 (m, 1H), 3.74 (s , 3H), 3.49 (s, 3H), 3.33 - 3.57 (m, 1H), 2.50 - 2.78 (m, 1H), 2.17 (s, 3H), 1.26 - 1.35 (m, 1H), 0.60 - 0.71 (m , 2H), 0.35 - 0.43 (m, 2H).

MS (ESI, pos.ion) m/z: 623.1 0 [M+H] ⁺ .

Example 75: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (2- cyclopropyl-2-yl) pyridin Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), 1-cyclopropyl-1-methylethylamine hydrochloride (59 mg, 0.43 mmol), 1-ethyl-(3-dimethylamino) propyl)carbodiimide hydrochloride (191 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL), Cool to 0°C, add N , N -diisopropylethylamine (0.17 mL, 1.00 mmol), react at room temperature for 16 h, add water (15 mL), extract with dichloromethane (5 mL × 3), the organic phase It was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 59 mg of white solid with a yield of 50%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.92 – 7.99 (m, 2H), 7.66 (d, J = 5.4 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.07 (s, 1H), 6.93 (s, 1H), 6.73 (t, J _FH = 71.4 Hz, 1H), 4.51 – 4.65 (m, 3H), 4.08 – 4.13 (m, 1H), 3.91 (d, J = 6.8 Hz, 2H), 3.66 (d, J = 10.5 Hz, 1H), 3.47 – 3.56 (m, 1H), 2.68 – 2.74 (m, 1H), 2.15 (s, 3H), 2.03 – 2.14 (m, 1H) ), 3.16 (s, 3H), 3.15 (s, 3H), 1.24 – 1.36 (m, 2H), 0.60 – 0.65 (m, 2H), 0.40 – 0.46 (m, 4H), 0.31 – 0.41 (m, 2H) ).

MS (ESI, pos.ion) m/z: 585.20 [M+H] ⁺ .

Example 76: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N- (cyclopropylmethyl) -N -methylpyridamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (98 mg, 0.19 mmol), 1-cyclopropyl- N -methylmethanamine hydrochloride (see Intermediate 9 for synthesis method) (63 mg, 0.52 mmol), 1-ethyl Alkyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (127 mg, 0.66 mmol) and N -hydroxy-7-azabenzotriazole (89 mg, 0.65 mmol) were dissolved in In dichloromethane (6 mL), N , N -diisopropylethylamine (0.3 mL, 2.0 mmol) was added dropwise to this solution at room temperature, stirred at room temperature for 6 h, water (50 mL) was added, and dichloromethane was added. Methane extraction (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain White solid 46 mg, yield 41%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.64 (br.s, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.32-7.40 (m, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 7.03 (t, J _FH = 75.0 Hz, 1H), 6.89 (d, J = 7.1 Hz, 1H), 4.30-4.56 (m, 3H), 4.05-4.10 (m, 1H), 3.91 (d, J = 6.4 Hz, 2H), 3.38-3.52 (m, 2H), 3.10-3.12 (m, 1H) , 2.92-3.03 (m, 3H), 2.55-2.66 (m, 1H), 2.03 (s, 3H), 1.85-1.96 (m, 1H), 1.23-1.29 (m, 1H), 0.95-1.06 (m, 1H), 0.53-0.60 (m, 2H), 0.37-0.51 (m, 2H), 0.30-0.36 (m, 2H), 0.22-0.29 (m, 1H), 0.02-0.09 (m, 1H).

MS (ESI, pos.ion) m/z: 571.20 [M+H] ⁺ .

Example 77: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (cyclohexylmethyl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), N -methyl-cyclohexylmethylamine (51 mg, 0.40 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Imine hydrochloride (196 mg, 1.02 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL) and added to this at 0°C N , N -diisopropylethylamine (0.17 mL, 1.00 mmol) was added dropwise to the solution, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), and extracted with dichloromethane (5 mL × 3). Dry over anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 39 mg of a pale yellow solid with a yield of 32%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.72 – 7.76 (m, 1H), 7.32 – 7.42 (m, 2H), 7.10 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H) ), 6.84 (d, J = 8.0 Hz, 1H), 6.60 (t, J _FH = 75.6 Hz, 1H), 4.48 – 4.65 (m, 3H), 3.91 – 3.95 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.53 – 3.58 (m, 1H), 3.36 – 3.41 (m, 1H), 3.27 – 3.36 (m, 1H), 3.18 – 3.22 (m, 1H), 3.08 (s, 1.5H) , 2.98(s, 1.5H), 2.52 – 2.60 (m, 1H), 2.39 – 2.47 (m, 1H), 2.12 (s, 3H), 1.71 – 1.78 (m, 3H), 1.54 – 1.66 (m, 6H) ), 1.26 – 1.34 (m, 1H), 1.02 – 1.17 (m, 2H), 0.62 – 0.67 (m, 2H), 0.33 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 613.30 [M+H] ⁺ .

Example 78: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -benzyl- N -methylpyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (80 mg, 0.16 mmol), N -methylbenzylamine (38 mg, 0.24 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt The acid salt (155 mg, 0.81 mmol) and N -hydroxy-7-azabenzotriazole (32 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL) and added dropwise to the solution at 0°C N , N -diisopropylethylamine (0.15 mL, 0.91 mmol) was added, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous sodium sulfate After drying, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 81 mg of white solid with a yield of 84%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 – 7.80 (m, 1H), 7.51 – 7.61 (m, 1H), 7.28 – 7.38 (m, 6H), 7.12 (d, J = 7.2 Hz , 1H), 6.79 – 6.90 (m, 2H), 6.62 (t, J _FH = 75.6 Hz, 1H), 4.50 – 4.83 (m, 4H), 4.08 – 4.14 (m, 1H), 3.84 – 3.96 (m, 1H), 3.87 (d, J = 6.3 Hz, 2H), 3.50 – 3.57 (m, 1H), 3.22 – 3.36 (m, 1H), 3.04 (s, 2H), 2.96 (s, 1H), 2.42 – 2.61 (m, 1H), 2.25 – 2.39 (m, 1H), 2.10 (s, 3H), 1.24 – 1.37 (m, 1H), 0.64 – 0.68 (m, 2H), 0.35 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 607.40 [M+H] ⁺ .

Example 79: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (pyrimidin-2-ylmethyl) pyridin Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (80 mg, 0.16 mmol), 2-aminomethylpyrimidine hydrochloride (36 mg, 0.25 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Imine hydrochloride (153 mg, 0.8 mmol) and N -hydroxy-7-azabenzotriazole (33 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL) and added to this at 0°C N , N -diisopropylethylamine (0.15 mL, 0.91 mmol) was added dropwise to the solution, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), and extracted with dichloromethane (5 mL × 3). It was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 71 mg of white solid with a yield of 74%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.64 (br.s, 1H), 8.71 (s, 2H), 8.42 (br.s, 1H), 8.09 – 8.16 (m, 1H), 7.77 – 7.87 (m, 1H), 7.36 – 7.44 (m, 1H), 7.09 – 7.18 (m, 2H), 6.81 – 6.91 (m, 2H), 6.60 (t, J _FH = 75.6 Hz, 1H), 4.88 – 5.05 (m, 2H), 4.56 – 4.79 (m, 3H), 3.78 – 3.96 (m, 3H), 3.40 – 3.49 (m, 1H), 3.24 – 3.32 (m, 1H), 2.65 – 2.75 (m, 1H) ), 2.46 – 2.55 (m, 1H), 2.05 (s, 3H), 1.23 – 1.37 (m, 1H), 0.62 – 0.69 (m, 2H), 0.34 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 595.40 [M+H] ⁺ .

Example 80: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -benzylpyridamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (98 mg, 0.19 mmol), benzylamine (43 mg, 0.4 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.0 mmol) and N -hydroxy-7-azabenzotriazole (40 mg, 0.3 mmol) were dissolved in dichloromethane (5 mL), to this solution was added dropwise N , N at 0°C -Diisopropylethylamine (0.16 mL, 0.97 mmol), reacted at room temperature for 12 h, washed with water (15 mL), then extracted with dichloromethane (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed , the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 82 mg of white solid with a yield of 71%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.50 (br.s, 1H), 8.68 (br.s, 1H), 8.17 (d, J = 7.5 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.24 – 7.44 (m, 6H), 7.13 (d, J = 8.1 Hz, 1H), 6.92 (s, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.63 (t , J _FH = 75.6 Hz, 1H), 4.78 – 4.89 (m, 2H), 4.58 – 4.71 (m, 3H), 3.84 – 3.93 (m, 1H), 3.89 (d, J = 6.8 Hz, 2H), 3.38 – 3.43 (m, 1H), 3.25 – 3.33 (m, 1H), 2.77 – 2.85 (m, 1H), 2.45 – 2.52 (m, 1H), 1.93 (s, 3H), 1.23 – 1.37 (m, 1H) , 0.65 – 0.69 (m, 2H), 0.36 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 593.20 [M+H] ⁺ .

Example 81: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N- (2,4-difluorophenyl) -N -methylpyridylamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (96 mg, 0.19 mmol), 1-(2,4-difluorophenyl) -N -methylmethanamine (73 mg, 0.46 mmol), 1-ethyl-(3- Dimethylaminopropyl)carbodiimide hydrochloride (131 mg, 0.68 mmol) and N -hydroxy-7-azabenzotriazole (85 mg, 0.62 mmol) were dissolved in dichloromethane (6 mL), N , N -diisopropylethylamine (0.3 mL, 2.0 mmol) was added at room temperature, stirred at room temperature for 13 h, washed with water (50 mL), and extracted with dichloromethane (5 mL × 3) , the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 52 mg of white solid, yield 42 %.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.62 (br.s, 1H), 7.85-7.92 (m, 1H), 7.38-7.51 (m, 3H), 7.24-7.36 (m, 1H), 7.09-7.13 (m, 2H), 7.05 (s, 1H), 7.03 (t, J _FH = 75.0 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.60-4.71 (m, 2H), 4.31-4.52 (m, 3H), 4.05-4.08 (m, 1H), 3.90 (d, J = 6.5 Hz, 2H), 3.39-3.50 (m, 2H), 2.90 (s, 3H), 2.55 -2.65 (m, 1H), 2.02 (s, 3H), 1.84-1.97 (m, 1H), 1.24-1.31 (m, 1H), 0.53-0.59 (m, 2H), 0.31-0.36 (m, 2H) .

MS (ESI, pos.ion) m/z: 643.20 [M+H] ⁺ .

Example 82: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (4- fluorobenzyl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), N -methyl-4-fluorobenzylamine (55 mg, 0.40 mmol), 1-ethyl-(3-dimethylaminopropyl)carbanium Diimine hydrochloride (196 mg, 1.02 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL) and added to the mixture at 0°C. N , N -diisopropylethylamine (0.17 mL, 1.00 mmol) was added dropwise to this solution, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), and extracted with dichloromethane (5 mL × 3). It was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 37 mg of white solid, yield 30%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.75 – 7.86 (m, 1H), 7.53 – 7.61 (m, 1H), 7.25 – 7.39 (m, 3H), 7.05 – 7.13 (m, 3H) , 6.82 – 6.96 (m, 2H), 6.62 (t, J _FH = 75.7 Hz, 1H), 4.48 – 4.73 (m, 4H), 4.11 – 4.19 (m, 0.5H), 3.85 – 3.95 (m, 0.5H) ), 3.88 ( d, J = 5.8 Hz, 2H), 3.51 – 3.57 (m, 1H), 3.25 – 3.38 (m, 1H), 3.02 (s, 2H), 2.96 (s, 1H), 2.27 – 2.60 ( m, 2H), 2.11 (s, 3H), 2.06 – 1.94 (m, 1H), 1.29 – 1.36 (m, 1H), 0.62 – 0.70 (m, 2H), 0.33 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 625.20 [M+H] ⁺ .

Example 83: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N- methyl -N- ((pyridin-2-yl)methyl)pyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (93 mg, 0.18 mmol), compound N -methyl-1-(pyridin-2-yl)methanamine dihydrochloride (63 mg, 0.52 mmol), 1-ethyl-( 3-Dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.63 mmol) and N -hydroxy-7-azabenzotriazole (87 mg, 0.64 mmol) in dichloromethane (6 mL), N , N -diisopropylethylamine (0.3 mL, 2.0 mmol) was added dropwise to this solution at room temperature, stirred at room temperature for 5 h, washed with water (50 mL), and washed with dichloromethane. Extraction (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain a white Solid 52 mg, yield 46%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.48-8.63 (m, 2H), 7.73-7.91 (m, 2H), 7.40-7.45 (m, 1H), 7.25-7.38 (m, 2H), 7.10-7.13 (m, 1H), 7.06 (s, 1H), 7.03 (t, J _FH = 74.7 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 4.67-4.74 (m, 2H), 4.26-4.50 (m, 3H), 4.03-4.10 (m, 1H), 3.90 (d, J = 6.4 Hz, 2H), 3.42-3.52 (m, 2H), 2.94-2.98 (m, 3H) , 2.55-2.65 (m, 1H), 2.03 (d, J = 3.8 Hz, 3H), 1.86-1.95 (m, 1H), 1.22-1.26 (m, 1H), 0.51-0.60 (m, 2H), 0.30 -0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 608.25 [M+H] ⁺ .

Example 84: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N , N -dicyclohexylpyridamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (86 mg, 0.17 mmol), dicyclohexylamine (96 mg, 0.53 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol) and N -hydroxy-7-azabenzotriazole (46 mg, 0.34 mmol) were dissolved in dichloromethane (6 mL), to this solution was added dropwise N at room temperature, N -diisopropylethylamine (0.3 mL, 2.0 mmol), stirred at room temperature for 13 h, added water (50 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, The concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 53 mg of white solid with a yield of 46%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.51-8.74 (m, 1H), 7.76-7.88 (m, 1H), 7.39-7.41 (m, 1H), 7.20-7.31 (m, 1H), 7.04-7.12 (m, 2H), 7.03 (t, J _FH = 75.0 Hz, 1H), 6.89 (d, J = 7.3 Hz, 1H), 4.30-4.52 (m, 3H), 4.02-4.13 ( m, 1H), 3.84-3.96 (m, 2H), 3.40-3.53 (m, 1H), 3.05-3.22 (m, 2H), 2.52-2.67 (m, 1H), 2.37-2.49 (m, 1H), 2.04 (s, 3H), 1.84-1.99 (m, 1H), 1.60-1.79 (m, 6H), 1.42-1.58 (m, 6H), 1.11-1.32 (m, 5H), 0.84-1.02 (m, 4H) ), 0.51-0.61 (m, 2H), 0.28-0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 667.30 [M+H] ⁺ .

Example 85: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -cyclohexyl- N- (cyclopropylmethyl)pyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), N- (cyclopropylmethyl)cyclohexylamine (60 mg, 0.39 mmol), 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (192 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (40 mg, 0.29 mmol) were dissolved in dichloromethane (5 mL) at 0°C N , N -diisopropylethylamine (0.17 mL, 1.00 mmol) was added dropwise to this solution, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 59 mg of white solid, yield 46% .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.66 – 7.76 (m, 1H), 7.53 (br.s, 1H), 7.26 – 7.37 (m, 2H), 7.08 (d, J = 6.4 Hz , 1H), 6.78 – 6.88 (m, 2H), 6.59 (t, J _FH = 75.5 Hz, 1H), 4.45 – 4.61 (m, 3H), 3.85 – 3.96 (m, 3H), 3.50 – 3.60 (m, 1H), 3.34 – 3.45 (m, 1H), 3.22 – 3.35 (m, 2H), 3.07 – 3.21 (m, 1H), 2.50 – 2.64 (m, 1H), 2.30 – 2.44 (m, 1H), 2.11 ( s, 3H), 1.84 – 1.98 (m, 6H), 1.34 – 1.54 (m, 4H), 1.14 – 1.33 (m, 2H), 0.58 – 0.66 (m, 2H), 0.47 – 0.56 (m, 2H), 0.29 – 0.39 (m, 4H).

MS (ESI, pos.ion) m/z: 639.35 [M+H] ⁺ .

Example 86: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (102 mg, 0.20 mmol), 4,4-difluoro- N -methylcyclohexylamine hydrochloride (56 mg, 0.30 mmol), 1-ethyl-(3-dimethyl aminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (55 mg, 0.40 mmol) in dichloromethane (5 mL) N , N -diisopropylethylamine (0.17 mL, 1.00 mmol) was added dropwise to this solution at 0°C, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), and extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 82 mg of a colored solid White, yield 63%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.71 – 7.82 (m, 1H), 7.48 (br.s, 1H), 7.35 – 7.45 (m, 2H), 7.10 (d, J = 6.4 Hz , 1H), 6.88 (s, 1H), 6.84 (d, J = 6.9 Hz, 1H), 6.60 (t, J _FH = 75.6 Hz, 1H), 4.49 – 4.68 (m, 3H), 3.87 – 3.96 (m , 1H), 3.86 (d, J = 5.5 Hz, 2H), 3.67 – 3.80 (m, 1H), 3.48 – 3.56 (m, 1H), 3.25 – 3.38 (m, 1H), 2.99 (s, 1.5H) , 2.86 (s, 1.5H), 2.42 – 2.51 (m, 2H), 2.13 – 2.27 (m, 2H), 2.11 (s, 3H), 1.84 – 1.96 (m, 6H), 1.24 – 1.35 (m, 1H) ), 0.59 – 0.68 (m, 2H), 0.31 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 635.30 [M+H] ⁺ .

Example 87: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (cyclopropylmethyl) - N - (4,4- difluoro-cyclohexyl) pyridin Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), N- (cyclopropylmethyl)-4,4-difluorocyclohexylamine hydrochloride (68 mg, 0.30 mmol), 1-ethyl- (3-Dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (54 mg, 0.40 mmol) in dichloro In methane (5 mL), N , N -diisopropylethylamine (0.2 mL, 1.00 mmol) was added dropwise to this solution at 0°C, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), and washed with two Chloromethane extraction (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1), 101 mg of light yellow solid was obtained, and the yield was 75%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.71 – 7.81 (m, 1H), 7.57 (br.s, 1H), 7.40 – 7.50 (m, 2H), 7.12 (d, J = 5.4 Hz , 1H), 6.90 (s, 1H), 6.86 (d, J = 6.9 Hz, 1H), 6.62 (t, J _FH = 75.6 Hz, 1H), 4.46 – 4.65 (m, 3H), 3.88 – 3.96 (m , 1H), 3.88 (d, J = 4.1 Hz, 2H), 3.67 – 3.82 (m, 1H), 3.53 – 3.58 (m, 1H), 3.26 – 3.37 (m, 2H), 3.16 – 3.27 (m, 1H) ), 2.46 – 2.55 (m, 2H), 2.13 – 2.23 (m, 2H), 2.13 (s, 3H), 1.94 – 2.05 (m, 6H), 1.55 – 1.73 (m, 1H), 1.26 – 1.34 (m , 1H), 0.81 – 0.94 (m, 1H), 0.62 – 0.70 (m, 2H), 0.52 – 0.62 (m, 1H), 0.35 – 0.44 (m, 4H).

MS (ESI, pos.ion) m/z: 675.30 [M+H] ⁺ .

Example 88: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carbamoylamino)methyl ) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine Amides

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid (67 mg, 0.21 mmol), 6-(amino methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methyl acyl pyridine dihydrochloride (94 mg, 0.33 mmol), 1- ethyl - (3-dimethylaminopropyl ) carbodiimide hydrochloride (88 mg, 0.46 mmol) and N -hydroxy-7-azabenzotriazole (54 mg, 0.39 mmol) were dissolved in dichloromethane (6 mL) at room temperature N , N -diisopropylethylamine (0.3 mL, 2.0 mmol) was added dropwise to this solution, stirred at room temperature for 17 h, washed with water (50 mL), and then extracted with dichloromethane (5 mL × 3), The organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 65 mg of white solid, yield 52% .

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 9.87 (s, 1H), 8.60 (t, J = 5.9 Hz, 1H), 7.82 - 7.93 (m, 1H), 7.34 - 7.50 (m , 2H), 7.04 - 7.07 (m, 1H), 6.99 (t, J _FH = 75.1 Hz, 1H), 6.86 - 6.89 (m, 1H), 6.75 (d, J = 9.8 Hz, 1H), 4.30 - 4.53 (m, 3H), 3.99 - 4.07 (m, 1H), 3.61 - 3.69 (m, 1H), 3.36 - 3.45 (m, 1H), 2.71 - 2.78 (m, 3H), 2.53 - 2.62 (m, 1H) , 1.91 - 2.15 (m, 3H), 2.02 (s, 3H), 1.65 - 1.90 (m, 7H).

MS (ESI, pos.ion) m/z: 581.30 [M+H] ⁺ .

Example 89: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carbamoylamino) Methyl) -N -cyclohexyl- N -picoline pyridamide

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carboxylic acid (67 mg, 0.20 mmol), 6 -(Aminomethyl) -N -cyclohexyl- N -picolinamide dihydrochloride (94 mg, 0.38 mmol, refer to Intermediate 6 for the synthesis method), 1-ethyl-(3-dimethylamino) propyl)carbodiimide hydrochloride (88 mg, 0.46 mmol) and N -hydroxy-7-azabenzotriazole (54 mg, 0.40 mmol) were dissolved in dichloromethane (6 mL), N , N -diisopropylethylamine (0.3 mL, 2.0 mmol) was added dropwise to this solution at room temperature, stirred at room temperature for 16 h, washed with water (50 mL), and then extracted with dichloromethane (5 mL × 3 ), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain a white solid 96 mg, yield 85%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.55 - 8.67 (m, 1H), 7.82 - 7.88 (m, 1H), 7.44 - 7.49 (m, 1H), 7.31 - 7.36 (m, 1H) 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.07 (t, J = 8.3 Hz, 1H), 7.02 (t, J _FH = 74.8 Hz, 1H), 6.85 - 6.93 (m, 1H), 4.26 - 4.45 (m, 3H), 4.01 - 4.15 (m, 3H), 3.40 - 3.52 (m, 2H), 2.86 (s, 1.6H), 2.70 (s, 1.4H), 2.57 - 2.66 (m, 1H) , 2.04 (d, J = 4.2 Hz, 3H), 1.86 - 1.96 (m, 1H), 1.40 - 1.81 (m, 8H), 1.31 - 1.37 (m, 3H), 1.21 - 1.29 (m, 2H).

MS (ESI, pos.ion) m/z: 573.35 [M+H] ⁺ .

Example 90: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-( ( N- (4,4-Difluorocyclohexyl)acetamido)methyl)pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150 mg, 0.41 mmol), N - (( 6- ( aminomethyl) pyridin-2-yl) methyl) - N - (4,4- difluoro-cyclohexyl) as acetamide dihydrochloride (166 mg, 0.45 mmol ), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (391 mg, 2.04 mmol) and N -hydroxy-7-azabenzotriazole (112 mg, 0.82 mmol) was dissolved in dichloromethane (15 mL), N , N -diisopropylethylamine (0.4 mL, 2.0 mmol) was added dropwise to this solution at 0 °C, the reaction was carried out at room temperature for 3 h, and washed with water. (15 mL), extracted with dichloromethane (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v ) = 30/1) to obtain 117 mg of white solid, yield 44%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.71 – 7.81 (m, 1H), 7.36 – 7.42 (m, 1H), 7.22 – 7.26 (m, 1H), 7.10 – 7.13 (m, 2H) ), 6.93 – 6.94 (m, 1H), 6.74 (t, J _FH = 75.7 Hz, 1H), 4.61 – 4.66 (m, 2H), 4.44 – 4.56 (m, 3H), 4.09 – 4.13 (m, 1H) , 4.00 – 4.11 (m, 1H), 3.93 – 3.95 (m, 2H), 3.67 (t, J = 10.6 Hz, 1H), 3.50 – 3.56 (m, 1H), 2.67 – 2.73 (m, 1H), 2.31 (s, 1H), 2.16 (s, 3H), 2.13 (s, 2H), 2.06 – 2.10 (m, 1H), 1.99 – 2.03 (m, 4H), 1.63 – 1.81 (m, 4H), 1.27 – 1.35 (m, 1H), 0.62 – 0.67 (m, 2H), 0.37 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 649.30 [M+H] ⁺ .

Example 91: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl acyl amino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino) Methyl)picolinic acid (76 mg, 0.15 mmol), 4,4-difluoro- N -methylcyclohexylamine hydrochloride (96 mg, 0.64 mmol), 1-ethyl-(3-dimethylamino) propyl)carbodiimide hydrochloride (96 mg, 0.50 mmol) and N -hydroxy-7-azabenzotriazole (46 mg, 0.34 mmol) were dissolved in dichloromethane (6 mL), N , N -diisopropylethylamine (0.3 mL, 2.0 mmol) was added dropwise to this solution at room temperature, stirred at room temperature for 17 h, added with water (50 mL), and extracted with dichloromethane (5 mL × 3) , the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 46 mg of white solid, yield 48 %.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.61 (t, J = 6.0 Hz, 1H), 7.84-7.89 (m, 1H), 7.34-7.51 (m, 2H), 7.12 (d , J = 8.2 Hz, 1H), 7.04-7.07 (m, 1H), 6.95 (t, J _FH = 74.8 Hz, 1H), 6.84-6.89 (m, 1H), 4.87-4.93 (m, 1H), 4.34 -4.52 (m, 3H), 4.01-4.12 (m, 1H), 3.41-3.52 (m, 2H), 2.71-2.87 (m, 3H), 2.58-2.67 (m, 1H), 2.04 (m, 3H) , 1.99-2.13 (m, 4H), 1.83-1.93 (m, 4H), 1.53-1.74 (m, 10H).

MS (ESI, pos.ion) m/z: 649.20 [M+H] ⁺ .

Example 92: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl acyl amino) methyl) - N - (cyclopropylmethyl) - N - (4,4- difluoro-cyclohexyl) pyridin Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopentyloxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino) Methyl)picolinic acid (76 mg, 0.15 mmol), N- (cyclopropylmethyl)-4,4-difluorocyclohexylamine hydrochloride (96 mg, 0.51 mmol), 1-ethyl-(3 -Dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol) and N -hydroxy-7-azabenzotriazole (46 mg, 0.34 mmol) were dissolved in dichloromethane ( 6 mL), add N , N -diisopropylethylamine (0.3 mL, 2.0 mmol) at room temperature, stir at room temperature for 17 h, add water (50 mL), extract with dichloromethane (5 mL × 3) , the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to column separation (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 66 mg of white solid with a yield of 65%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.61 (t, J = 6.0 Hz, 1H), 7.83-7.87 (m, 1H), 7.31-7.51 (m, 2H), 7.12 (d , J = 8.4 Hz, 1H), 7.04-7.08 (m, 1H), 6.95 (t, J _FH = 74.8 Hz, 1H), 6.84-6.91 (m, 1H), 4.88-4.93 (m, 1H), 4.34 -4.50 (m, 3H), 4.05-4.12 (m, 1H), 3.40-3.52 (m, 2H), 3.18-3.25 (m, 1H), 3.08-3.12 (m, 1H), 2.58-2.65 (m, 1H), 2.39 (d, J = 6.7 Hz, 2H), 2.04 (s, 3H), 1.96-2.10 (m, 4H), 1.84-1.92 (m, 4H), 1.74-1.80 (m, 8H), 1.32 -1.39 (m, 1H), 0.37-0.40 (m, 2H), 0.09-0.11 (m, 2H).

MS (ESI, pos.ion) m/z: 689.35 [M+H] ⁺ .

Example 93: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-ethoxyphenyl)pyrrolidine-2-carbamoylamino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carbamoylamino)methyl) -N -(4,4-Difluorocyclohexyl) -N -picolinamide (60 mg, 0.10 mmol), potassium carbonate (36 mg, 0.26 mmol) in N , N -dimethylformamide (3 mL), add iodoethane (0.1 mL, 1.0 mmol) at room temperature, react at 70 °C for 17 h, add water (50 mL), extract with ethyl acetate (5 mL × 3), and dry the organic phase with anhydrous sodium sulfate , the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 33 mg of white solid with a yield of 52%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.60 (t, J = 5.9 Hz, 1H), 7.84-7.90 (m, 1H), 7.34-7.51 (m, 2H), 7.05-7.14 (m, 2H), 7.02 (t, J _FH = 74.9 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.33-4.51 (m, 3H), 4.08-4.12 (m, 3H), 3.41 -3.52 (m, 2H), 2.71-2.87 (m, 3H), 2.58-2.64 (m, 1H), 2.03 (s, 3H), 1.63-2.12 (m, 10H), 1.34 (t, J = 6.7 Hz , 3H).

MS (ESI, pos.ion) m/z: 609.30 [M+H] ⁺ .

Example 94: Compound 6-((( 2R )-1-Acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl) - N -Cyclohexyl- N -picolinamide

The compound 6-((( 2R )-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl)picolinic acid ( 80 mg, 0.16 mmol), N -methylcyclohexylamine (36 mg, 0.32 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (156 mg, 0.81 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL), and N , N -diisopropylethylamine was added dropwise at 0°C (0.13 mL, 0.79 mmol), reacted at room temperature for 22 h, washed with water (15 mL), then extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column layer 42 mg of white solid was obtained, and the yield was 43%.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.76 (s, 1H), 7.51 – 7.54 (m, 1H), 7.35 – 7.38 (m, 2H), 7.12 – 7.28 (m, 3H), 6.56 (t, J _FH = 73.5 Hz, 1H), 6.53 (t, J _FH = 73.5 Hz, 1H), 4.50 – 4.63 (m, 3H), 3.99 (dd, J = 9.9, 7.6 Hz, 1H), 3.58 ( t, J = 10.6 Hz, 1H), 3.30 – 3.46 (m, 2H), 3.00 (s, 2H), 2.84 (s, 1H), 2.58 – 2.64 (m, 1H), 2.40 – 2.47 (m, 1H) , 2.15 (s, 3H), 1.70 – 1.85 (m, 6H), 1.48 – 1.56 (m, 4H).

MS (ESI, pos.ion) m/z: 595.30 [M+H] ⁺ .

Example 95: Compound 6-((( 2R )-1-Acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl) - N- (4,4-Difluorocyclohexyl) -N -picoline pyridamide

The compound 6-((( 2R )-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl)picolinic acid ( 80 mg, 0.16 mmol), 4,4-difluoro- N -methylcyclohexylamine hydrochloride (36 mg, 0.19 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Imine hydrochloride (151 mg, 0.79 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL) and added to this at 0°C N , N -diisopropylethylamine (0.13 mL, 0.79 mmol) was added dropwise to the solution, the reaction was carried out at room temperature for 15 h, washed with water (15 mL), and extracted with dichloromethane (5 mL × 3). It was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 23 mg of white solid with a yield of 22%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.79 (br.s, 1H), 7.36 – 7.50 (m, 3H), 7.13 – 7.26 (m, 3H), 6.56 (t, J _FH = 73.6 Hz, 1H), 6.53 (t, J _FH = 73.6 Hz, 1H), 4.51 – 4.67 (m, 4H), 3.93 – 4.03 (m, 1H), 3.50 – 3.62 (m, 1H), 3.30 – 3.46 (m , 1H), 3.02 (s, 1H), 2.90 (s, 2H), 2.45 – 2.64 (m, 2H), 2.05 – 2.29 (m, 2H), 2.16 (s, 3H), 1.91 – 2.04 (m, 6H) ).

MS (ESI, pos.ion) m/z: 631.30 [M+H] ⁺ .

Example 96: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -cyclopentyl- N -methylpyridylamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), N -methylcyclopentylamine hydrochloride (55 mg, 0.410 mmol), 1-ethyl-(3-dimethylaminopropyl)carbohydride Diimine hydrochloride (191 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL) and added to the solution at 0 °C. N , N -diisopropylethylamine (0.17 mL, 1.00 mmol) was added dropwise to this solution, the reaction was carried out at room temperature for 12 h, washed with water (15 mL), and extracted with dichloromethane (5 mL × 3). It was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 59 mg of white solid, with a yield of 50%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 (s, 1H), 7.50 (br.s, 1H), 7.35 – 7.41 (m, 2H), 7.12 (d, J = 7.1 Hz, 1H ), 6.90 (s, 1H), 6.86 (d, J = 7.1 Hz, 1H), 6.62 (t, J _FH = 75.6 Hz, 1H), 5.02 – 5.10 (m, 0.4H), 4.48 – 4.65 (m, 3H), 3.99 – 4.09 (m, 0.6H), 3.91 – 3.97 (m, 1H), 3.88 (d, J = 5.8 Hz, 2H), 3.55 – 3.61 (m, 1H), 3.29 – 3.38 (m, 1H) ), 3.00 (s, 2H), 2.85 (s, 1H), 2.56 – 2.61 (m, 1H), 2.40 – 2.47 (m, 1H), 2.14 (s, 3H), 1.68 – 1.84 (m, 8H), 1.26 – 1.34 (m, 1H), 0.65 – 0.68 (m, 2H), 0.35 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 585.30 [M+H] ⁺ .

Example 97: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxylamido)methyl) -N -cyclobutyl- N -methylpyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (114 mg, 0.23 mmol), N -methylcyclobutylamine hydrochloride (48 mg, 0.40 mmol), 1-ethyl-(3-dimethylaminopropyl)carbohydride Diimine hydrochloride (191 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 °C, N , N -diisopropylethylamine (0.17 mL, 1.00 mmol) was added, the reaction was carried out at room temperature for 12 h, water (15 mL) was added, extracted with dichloromethane (5 mL × 3), and the organic phase was dried over anhydrous sodium sulfate , the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 82 mg of white solid with a yield of 63%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.74 (s, 1H), 7.58 (br.s, 1H), 7.29 – 7.39 (m, 2H), 7.12 (d, J = 5.8 Hz, 1H ), 6.89 (s, 1H), 6.85 (d, J = 6.6 Hz, 1H), 6.61 (t, J _FH = 75.6 Hz, 1H), 4.97 – 5.12 (m, 0.4H), 4.48 – 4.66 (m, 3H), 4.15 – 4.28 (m, 0.6H), 3.78 – 3.96 (m, 3H), 3.51 – 3.63 (m, 1H), 3.25 – 3.39 (m, 1H), 3.09 (s, 2H), 2.94 (s , 1H), 2.52 – 2.63 (m, 1H), 2.35 – 2.45 (m, 1H), 2.12 (s, 3H), 1.94 – 2.04 (m, 4H), 1.62 – 1.74 (m, 2H), 1.26 – 1.34 (m, 1H), 0.58 – 0.68 (m, 2H), 0.31 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 571.30 [M+H] ⁺ .

Example 98: Compound 6-((( 2R )-1-Acetyl-4-(3-(2,2-difluoroethoxy)-4-(difluoromethoxy)phenyl)pyrrole alkyl-2-acyl-amino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carbamoylamino)methyl) -N -(4,4-Difluorocyclohexyl) -N -picolinamide (53 mg, 0.09 mmol), potassium carbonate (36 mg, 0.26 mmol) in N , N -dimethylformamide (3 mL), 2-bromo-1,1-difluoroethane (0.1 mL, 1.0 mmol) was added to this solution at room temperature, reacted at 70 °C for 12 h, washed with water (50 mL), and then ethyl acetate Extraction (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain a white Solid 31 mg, yield 52%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.60 - 8.63 (m, 1H), 7.81 - 7.95 (m, 1H), 7.31 - 7.51 (m, 2H), 7.12 - 7.24 (m, 2H), 7.04 (t, J _FH = 74.9 Hz, 1H), 6.91 - 7.01 (m, 1H), 6.40 (t, J _FH = 54.6 Hz, 1H), 4.30 - 4.57 (m, 5H), 4.09 - 4.23 (m, 1H), 3.41 - 3.74 (m, 3H), 2.86 (s, 1.5H), 2.73 (s, 1.5H), 2.55 - 2.67 (m, 1H), 1.95 - 2.15 (m, 6H), 1.62 - 1.88 (m, 6H).

MS (ESI, pos.ion) m/z: 645.30 [M+H] ⁺ .

Example 99: Compound 6-((( 2R )-1-Acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl) - N- (4,4-dideuterocyclohexyl) -N -methylpyridamide

The compound 6-((( 2R )-1-acetyl-4-(3,4-bis(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino)methyl)picolinic acid ( 100 mg, 0.20 mmol), 4,4-dideutero- N -methylcyclohexylamine hydrochloride (67 mg, 0.44 mmol), 1-ethyl-(3-dimethylaminopropyl)carbohydride Imine hydrochloride (193 mg, 1.01 mmol) and N -hydroxy-7-azabenzotriazole (53 mg, 0.39 mmol) were dissolved in dichloromethane (5 mL) and added to this at 0°C N , N -diisopropylethylamine (0.26 mL, 1.60 mmol) was added dropwise to the solution, the reaction was carried out at room temperature for 12 h, water (15 mL) was added, extracted with dichloromethane (5 mL × 3), and the organic phase was washed with anhydrous It was dried over sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 66 mg of white solid with a yield of 55%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.92 (br.s, 1H), 7.58 – 7.63 (m, 1H), 7.40 (d, J = 6.7 Hz, 1H), 7.25 – 7.34 ( m, 3H), 6.86 (t, J _FH = 73.6 Hz, 1H), 6.82 (t, J _FH = 73.6 Hz, 1H), 4.48 – 4.65 (m, 3H), 4.10 – 4.20 (m, 1H), 3.61 – 3.69 (m, 1H), 3.51 – 3.60 (m, 1H), 3.36 – 3.46 (m, 1H), 3.00 (s, 1.6H), 2.82 (s, 1.4H), 2.68 – 2.79 (m, 1H) , 2.17 (s, 3H), 2.01 – 2.12 (m, 1H), 1.71 – 1.88 (m, 4H), 1.53 – 1.66 (m, 2H), 1.37 – 1.49 (m, 1H), 1.04 – 1.12 (m, 1H).

MS (ESI, pos.ion) m/z: 597.70 [M+H] ⁺ .

Example 100: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (cyclohexyl of 4,4-dideutero-yl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (90 mg, 0.18 mmol), 4,4-dideutero- N -methylcyclohexylamine hydrochloride (42 mg, 0.28 mmol), 1-ethyl-(3-dimethyl aminopropyl)carbodiimide hydrochloride (173 mg, 0.9 mmol) and N -hydroxy-7-azabenzotriazole (49 mg, 0.36 mmol) in dichloromethane (5 mL) N , N -diisopropylethylamine (0.21 mL, 1.3 mmol) was added dropwise to this solution at 0°C, reacted at room temperature for 10 h, added water (25 mL), extracted with dichloromethane (10 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 46 mg of white solid, which was collected rate 42%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.92 (s, 1H), 7.57 – 7.64 (m, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.10 (s, 1H), 6.92 – 6.95 (m, 1H), 6.75 (t, J _FH = 75.6 Hz, 1H), 4.51 – 4.64 (m, 3H), 4.08 – 4.15 (m, 1H), 3.94 (d, J = 5.7 Hz, 2H), 3.67 (t, J = 10.2 Hz, 1H), 3.46 – 3.56 (m, 1H), 3.36 – 3.45 (m, 1H), 3.00 (s, 1.7 H), 2.81 (s, 1.3H), 2.64 – 2.75 (m, 1H), 2.17 (s, 3H), 2.01 – 2.12 (m, 1H), 1.71 – 1.88 (m, 4H), 1.53 – 1.65 (m , 2H), 1.35 – 1.47 (m, 2H), 1.03 – 1.11 (m, 1H), 0.62 – 0.68 (m, 2H), 0.38 – 0.42 (m, 2H).

MS (ESI, pos.ion) m/z: 601.30 [M+H] ⁺ .

Example 101: Compound 6-((( 2R )-1-acetoxy-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy) yl) phenyl) pyrrolidine-2-acyl-amino) methyl) - N - (cyclohexyl of 4,4-dideutero-yl) - N - methylpyridine Amides

Compound 6-(((2 R )-1-acetyl-4-(3-(cyclopropyl(1,1-dideutero)methoxy)-4-(difluoromethoxy)phenyl )pyrrolidine-2-carbamoylamino)methyl)picolinic acid (90 mg, 0.18 mmol), 4,4-dideutero- N -methylcyclohexylamine hydrochloride (40 mg, 0.26 mmol), 1- Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (175 mg, 0.91 mmol) and N -hydroxy-7-azabenzotriazole (53 mg, 0.39 mmol) were dissolved In dichloromethane (5 mL), after cooling to 0 ℃, N , N -diisopropylethylamine (0.26 mL, 1.6 mmol) was added, the reaction was carried out at room temperature for 15 h, water (15 mL) was added, dichloromethane Extraction (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, concentrated, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain a white Solid 46 mg, yield 43%.

¹ H NMR (600 MHz, CD ₃ OD) δ (ppm): 7.90 – 7.94 (m, 1H), 7.57 – 7.63 (m, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 7.09 (s, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.75 (t, J _FH = 75.8 Hz, 1H), 4.47 – 4.64 (m, 3H), 4.09 – 4.14 (m, 1H), 3.66 (t, J = 10.4 Hz, 1H), 3.47 – 3.55 (m, 1H), 3.37 – 3.44 (m, 1H), 3.00 (s, 1.5H), 2.81 (s, 1.5H), 2.67 – 2.72 (m, 1H), 2.17 (s, 3H), 2.07 – 2.12 (m, 1H), 1.73 – 1.87 (m, 4H), 1.51 – 1.66 (m, 2H), 1.38 – 1.45 (m, 1H), 1.28 – 1.36 (m, 1H), 1.05 – 1.10 (m, 1H), 0.63 – 0.66 (m, 2H), 0.38 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 603.35 [M+H] ⁺ .

Example 102: Compound 6-(((2 R )-1-acetoxy-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy) yl) phenyl) pyrrolidine-2-acyl-amino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine Amides

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropyl-(1,1-dideutero)methoxy)-4-(difluoromethoxy)benzene yl)pyrrolidine-2-carbamoylamino)methyl)picolinic acid (90 mg, 0.18 mmol), 4,4-difluoro- N -methylcyclohexylamine hydrochloride (49 mg, 0.27 mmol), 1 -Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (172 mg, 0.9 mmol) and N -hydroxy-7-azabenzotriazole (49 mg, 0.36 mmol) It was dissolved in dichloromethane (5 mL), cooled to 0 °C, N , N -diisopropylethylamine (0.21 mL, 1.3 mmol) was added, the reaction was carried out at room temperature for 18 h, water (15 mL) was added, and dichloromethane was added. Methane extraction (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, concentrated, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain White solid 77 mg, yield 68%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.90 – 7.95 (m, 1H), 7.58 – 7.63 (m, 1H), 7.42 – 7.47 (m, 1H), 7.12 (d, J = 7.9 Hz, 1H), 7.09 (s, 1H), 6.91 – 6.95 (m, 1H), 6.75 (t, J _FH = 75.6 Hz, 1H), 4.45 – 4.64 (m, 3H), 4.07 – 4.14 (m, 1H) ), 3.66 – 3.78 (m, 0.5H), 3.66 (t, J = 10.5 Hz, 1H), 3.46 – 3.57 (m, 1H), 3.33 – 3.42 (m, 0.5H), 3.00 (s, 1.5H) , 2.84 (s, 1.5H), 2.64 – 2.74 (m, 1H), 2.16 (s, 3H), 2.01 – 2.12 (m, 1H), 1.80 – 2.10 (m, 8H), 1.29 – 1.38 (m, 1H) ), 0.61 – 0.67 (m, 2H), 0.35 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 637.80 [M+H] ⁺ .

Example 103: Compound 6 - (((2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-2 methyl acyl amino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine Amides

Compound (2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-methoxy - d ₃ - phenyl) pyrrolidine-2-carboxylic acid (45 mg, 0.14 mmol), 6- (aminomethyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methyl acyl pyridine dihydrochloride (62 mg, 0.17 mmol), 1- ethyl - (3 -Dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.69 mmol) and N -hydroxy-7-azabenzotriazole (39 mg, 0.29 mmol) were dissolved in dichloromethane ( 10 mL), cooled to 0 °C, added N , N -diisopropylethylamine (0.16 mL, 0.97 mmol), reacted at room temperature for 11 h, added water (20 mL), stirred for 5 min, and extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain White solid 32 mg, yield 39%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 – 7.82 (m, 1H), 7.37 – 7.49 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H) ), 6.87 (d, J = 7.9 Hz, 1H), 6.55 (t, J _FH = 75.2 Hz, 1H), 4.64 – 4.72 (m, 0.6H), 4.54 – 4.64 (m, 3H), 3.95 – 3.99 ( m, 1H), 3.72 – 3861 (m, 0.4H), 3.55 – 3.61 (m, 1H), 3.30 – 3.41 (m, 1H), 3.02 (s, 1.3H), 2.89 (s, 1.7H), 2.50 – 2.61 (m, 2H), 2.17 – 2.27 (m, 2H), 2.15 (s, 3H), 1.85 – 2.03 (m, 6H).

MS (ESI, pos.ion) m/z: 598.40 [M+H] ⁺ .

Example 104: Compound 6-((( 2R )-1-Acetyl-4-(2,2-difluorobenzo[ d ][1,3]dioxocen-5-yl)pyrrolidine- 2-acyl-amino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine Amides

The compound ( 2R )-1-acetyl-4-(2,2-difluorobenzo[ d ][1,3]dioxoc-5-yl)pyrrolidine-2-carboxylic acid (60 mg , 0.19 mmol), 6- (aminomethyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methyl acyl pyridine dihydrochloride (82 mg, 0.23 mmol), 1- ethyl - (3-Dimethylaminopropyl)carbodiimide hydrochloride (182 mg, 0.95 mmol) and N -hydroxy-7-azabenzotriazole (53 mg, 0.39 mmol) in dichloro In methane (6 mL), after cooling to 0 °C, N , N -diisopropylethylamine (0.23 mL, 1.4 mmol) was added, the reaction was carried out at room temperature for 11 h, water (20 mL) was added and stirred for 5 min. Extraction with methane (15 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) , 72 mg of white solid was obtained, and the yield was 65%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.72 – 7.83 (m, 1H), 7.57 (br.s, 1H), 7.34 – 7.48 (m, 2H), 6.94 – 7.07 (m, 3H) , 4.47 – 4.72 (m, 3.6H), 3.90 – 4.02 (m, 1H), 3.70 – 3.80 (m, 0.4H), 3.52 – 3.57 (m, 1H), 3.29 – 3.43 (m, 1H), 3.01 ( s, 1.3H), 2.88 (s, 1.7H), 2.46 – 2.56 (m, 2H), 2.12 – 2.25 (m, 2H), 2.13 (s, 3H) , 1.90 – 1.99 (m, 6H).

MS (ESI, pos.ion) m/z: 579.10 [M+H] ⁺ .

Example 105: Compound 6-((( 2R )-1-Acetyl-4-(5-((cyclopropylmethyl)-hydroxyamino)-4-(difluoromethoxy)-2- (acyl methanesulfonamide) phenyl) pyrrolidine-2-acyl-amino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine Amides

The compound ( 2R )-1-acetyl-4-(5-((cyclopropylmethyl)-hydroxyamino)-4-(difluoromethoxy)-2-(methylsulfonyl)benzene yl) pyrrolidine-2-carboxylic acid (60 mg, 0.13 mmol), 6- ( aminomethyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methyl acyl pyridine dihydrochloride ( 55 mg, 0.15 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (164 mg, 0.65 mmol) and N -hydroxy-7-azabenzotriazepine azole (35 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C, N , N -diisopropylethylamine (0.15 mL, 0.91 mmol) was added, and the reaction was carried out at room temperature for 12 h, Water (20 mL) was added, stirred for 5 min, the organic phase was separated, the aqueous phase was extracted with dichloromethane (5 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluting) Reagent: dichloromethane/methanol (v/v) = 30/1) to obtain 63 mg of white solid with a yield of 67%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.74 – 7.87 (m, 1H), 7.52 – 7.63 (m, 1H), 7.37 – 7.49 (m, 2H), 6.97 (s, 1H), 6.69 (s, 1H), 6.50 (t, J _FH = 73.6 Hz, 1H), 4.54 – 4.74 (m, 4H), 4.30 – 4.39 (m, 1H), 3.99 – 4.08 (m, 1H), 3.64 – 3.81 ( m, 1H), 3.46 – 3.53 (m, 1H), 3.25 (s, 3H), 2.89 – 3.02 (m, 5H), 2.45 – 2.60 (m, 2H), 2.12 – 2.27 (m, 2H), 2.12 ( s, 3H), 1.83 – 2.04 (m, 6H) , 1.05 – 1.13 (m, 1H), 0.55 – 0.65 (m, 2H), 0.22 – 0.34 (m, 2H).

MS (ESI, pos.ion) m/z: 728.80 [M+H] ⁺ .

Example 106: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - methyl - N - ((1 r, 4 R) -4- methylcyclohexyl) pyridin Amides

Step 1: Synthesis of compound tert-butyl(( 1r , 4r )-4-methylcyclohexyl)carbamate

( 1r , 4r )-4-methylcyclohexylamine (800 mg, 7.06 mmol) and N , N -diisopropylethylamine (1.4 mL, 8.50 mmol) were dissolved in dichloromethane (8 mL) , add di-tert-butyl dicarbonate (1.7 g, 7.80 mmol) under ice bath, react at room temperature for 9 h, add water (20 mL) and stir for 5 min, separate the organic phase, dry the organic phase with anhydrous sodium sulfate, remove the solvent, The concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 20/1) to obtain 612 mg of white solid with a yield of 40%.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 4.36 (brs, 1H), 3.31 – 3.41 (m, 1H), 1.97 – 2.00 (m, 2H), 1.69 – 1.72 (m, 2H), 1.46 (s, 9H), 1.27 – 1.37 (m, 1H), 1.01 – 1.14 (m, 4H), 0.90 (d, J = 6.5 Hz, 3H).

MS (ESI, pos.ion) m/z: 158.25 [M-55] ⁺ .

Step 2: Synthesis of compound tert-butylmethyl(( 1r , 4r )-4-methylcyclohexyl)carbamate

tert-Butyl(( 1r , 4r )-4-methylcyclohexyl)carbamate (300 mg, 1.41 mmol) was dissolved in anhydrous N , N -dimethylformamide (8 mL), Add 60% sodium hydride (84 mg, 2.10 mmol) under ice bath, react at room temperature for 30 min, add iodomethane (260 mg, 1.83 mmol) under ice bath, react at room temperature for 9 h, add water (25 mL), add acetic acid Ethyl ester extraction (10 mL × 3), the organic phase was separated, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 25/1) to obtain 129 mg of a colorless liquid with a yield of 40%.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 3.75 – 4.04 (m, 1H), 2.72 (s, 3H), 1.73 – 1.76 (m, 2H), 1.64 – 1.67 (m, 2H), 1.39 – 1.51 (m, 2H), 1.47 (s, 9H), 1.25 – 1.34 (m, 1H), 1.01 – 1.10 (m, 2H), 0.90 (d, J = 6.5 Hz, 3H).

MS (ESI, pos.ion) m/z: 172.25 [M-55] ⁺ .

Step 3: Synthesis of compound (1r , 4r ) -N ,4-dimethylcyclohexylamine hydrochloride

Compound tert-butylmethyl(( 1r , 4r )-4-methylcyclohexyl)carbamate (120 mg, 0.53 mmol) was dissolved in dichloromethane (3 mL) solution, and 4 mol/L HCl was added The ethyl acetate solution (6 mL) was stirred at room temperature for 1 h, and concentrated under reduced pressure to obtain 83 mg of a white solid with a yield of 96%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 2.94 – 3.00 (m, 1H), 2.69 (s, 3H), 2.11 – 2.14 (m, 2H), 1.85 – 1.88 (m, 2H), 1.32 – 1.43 (m, 3H), 1.02 – 1.12 (m, 2H), 0.95 (d, J = 6.5 Hz, 3H).

MS (ESI, pos.ion) m/z: 128.30 [M+H-HCl] ⁺ .

Step 4: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Synthesis of Carboxylamido)methyl) -N -methyl- N -((1 r ,4 R )-4-methylcyclohexyl)pyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), ( 1r , 4r ) -N ,4-dimethylcyclohexylamine hydrochloride (59 mg, 0.36 mmol), 1-ethyl-( 3-Dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1.00 mmol) and N -hydroxy-7-azabenzotriazole (43 mg, 0.32 mmol) in dichloromethane (5 mL), cooled to 0 °C, added N , N -diisopropylethylamine (0.17 mL, 1.00 mmol), reacted at room temperature for 6 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 41 mg of white solid , the yield is 33%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.72 – 7.80 (m, 1H), 7.34 – 7.50 (m, 3H), 7.12 (d, J = 7.6 Hz, 1H), 6.90 (s, 1H) ), 6.86 (d, J = 7.7 Hz, 1H), 6.62 (t, J _FH = 75.5 Hz, 1H), 4.47 – 4.65 (m, 3.6H), 3.90 – 3.99 (m, 1H), 3.88 (d, J = 6.6 Hz, 2H), 3.55 – 3.62 (m, 1H), 3.29 – 3.45 (m, 1.4H), 3.00 (s, 1.7H), 2.83 (s, 1.3H), 2.53 – 2.63 (m, 1H) ), 2.38 – 2.48 (m, 1H), 2.14 (s, 3H), 1.52 – 1.72 (m, 5H), 1.14 – 1.37 (m, 5H), 0.94 (d, J = 5.5 Hz, 1.5H), 0.83 (d, J = 5.5 Hz, 1.5H), 0.63 – 0.70 (m, 2H), 0.33 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 613.45 [M+H] ⁺ .

Example 107: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Carboxyamino)methyl) -N -methyl- N- (4-chlorophenyl)pyridinamide

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), N -methyl-4-chloroaniline (70 mg, 0.50 mmol), 1-ethyl-(3-dimethylaminopropyl)carboamide Imine hydrochloride (251 mg, 1.31 mmol) and N -hydroxy-7-azabenzotriazole (54 mg, 0.40 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 °C, added N , N -diisopropylethylamine (183 mg, 1.42 mmol), reacted at room temperature for 22 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was dried over anhydrous sodium sulfate , the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 82 mg of white solid with a yield of 65%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.64 (br.s, 1H), 7.35 - 7.48 (m, 1H), 7.18 - 7.28 (m, 2H), 6.97 - 7.16 (m, 4H) , 6.83 - 6.95 (m, 2H), 6.63 (t, J _FH = 75.5 Hz, 1H), 4.42 - 4.51 (m, 3H), 3.88 - 4.00 (m, 3H), 3.51 - 3.65 (m, 1H), 3.51 (s, 3H), 3.29 - 3.45 (m, 1H), 2.51 - 2.64 (m, 1H), 2.35 - 2.63 (m, 1H), 2.15 (s, 3H), 1.26 - 1.35 (m, 1H), 0.64 - 0.71 (m, 2H), 0.36 - 0.43 (m, 2H).

MS (ESI, pos.ion) m/z: 627.10 [M+H] ⁺ .

Example 108: Compound 6-((( 2R )-1-Acetyl-4-(3-(isopropoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl acyl amino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methylpyridine Amides

Step 1: Compound ( R )-6-((1-Acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1 H - pyrrole-2-acyl-amino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - synthesis of Amides methylpyridine

The compound ( R )-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro- 1H -pyrrole-2- carboxylic acid (300 mg, 0.74 mmol), 6- ( aminomethyl) - N - (of 4,4-difluoro-cyclohexyl) - N - methyl acyl pyridine dihydrochloride (301 mg, 0.85 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (718 mg, 3.75 mmol) and N -hydroxy-7-azabenzotriazole (203 mg, 1.49 mmol) ) was dissolved in dichloromethane (10 mL), cooled to 0 °C, N , N -diisopropylethylamine (0.9 mL, 5.0 mmol) was added, the reaction was carried out at room temperature for 7 h, washed with water (20 mL) and stirred , the organic phase was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 387 mg of white solid , the yield is 77%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.75 – 7.81 (m, 1H), 7.41 – 7.49 (m, 5H), 7.34 – 7.40 (m, 2H), 7.18 – 7.20 (m, 1H) , 7.07 – 7.10 (m, 1H), 6.93 – 7.01 (m, 1H), 6.61 (t, J _FH = 74.9 Hz, 1H), 6.18 – 6.23 (m, 1H), 5.37 – 5.41 (m, 0.7H) , 5.23 – 5.27 (m, 0.3H), 5.17 (s, 2H), 4.66 – 4.74 (m, 2H), 4.55 – 4.65 (m, 3H), 2.87 (s, 2H), 2.78 (s, 1H), 2.24 (s, 3H), 2.07 (s, 1H), 2.06 – 2.16 (m, 2H), 1.82 – 2.04 (m, 6H).

MS (ESI, pos.ion) m/z: 669.15 [M+H] ⁺ .

Step 2: Compound 6-((( 2R )-1-Acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carbamoylamino)methyl) - Synthesis of N- (4,4-difluorocyclohexyl) -N-picolinamide

Compound (R) -6 - ((1- acetyl-4- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -2,5-dihydro -1 H - acyl pyrrole-2-ylamino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - Amides methylpyridine (380 mg, 0.57mmol) was dissolved in methanol (10 mL), was added Pd / C (53 mg) was passed into hydrogen and reacted at room temperature for 12 h, the catalyst was removed by filtration, the filtrate was concentrated, and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 25/1) to obtain 316 mg of white solid, yield 95%.

MS (ESI, pos.ion) m/z: 581.10 [M+H] ⁺ .

Step 3: Compound 6-((( 2R )-1-Acetyl-4-(3-(isopropoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate amino) methyl) - N - (of 4,4-difluoro-cyclohexyl) - N - acyl amine-methylpyridine

The 6 - (((2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-hydroxyphenyl) pyrrolidine-2-acyl-amino) methyl) - N - (4,4-Difluorocyclohexyl) -N -picolinamide (70 mg, 0.12 mmol), 2-iodopropane (61 mg, 0.36 mmol), potassium carbonate (83 mg, 0.60 mmol) were dissolved in dry In a solution of N , N -dimethylformamide (3mL), react at 80°C for 2 h, add water (30mL), extract with ethyl acetate (10mL × 3), dry the organic phase with anhydrous sodium sulfate, concentrate , and separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 63 mg of white solid with a yield of 83%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.91 – 7.95 (m, 1H), 7.59 – 7.64 (m, 1H), 7.42 – 7.48 (m, 1H), 7.12 – 7.13 (m, 2H) ), 6.94 (d, J = 8.0 Hz, 1H), 6.70 (t, J _FH = 75.7 Hz, 1H), 4.61 – 4.70 (m, 2H), 4.45 – 4.55 (m, 2H), 4.10 – 4.15 (m , 1H), 3.70 – 3.77 (m, 1H), 3.52 – 3.69 (m, 1H), 3.47 – 3.58 (m, 1H), 3.30 (s, 1.5H), 2.84 (s, 1.5H), 2.66 – 2.74 (m, 1H), 2.16 (s, 3H), 2.01 – 2.08 (m, 1H), 1.76 – 2.00 (m, 8H), 1.35 (d, J = 5.7 Hz, 6H).

MS (ESI, pos.ion) m/z: 623.20 [M+H] ⁺ .

Example 109: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 - A XI) methyl) - N - (9- amino-5,7-dihydro-dibenzo [c, e] Zhuo oxa-3-yl) pyridin Amides

Step 1: Synthesis of compound 4,4'-dinitro-[1,1'-biphenyl]-2,2'-dicarbaldehyde

Combine 2-bromo-5-nitrobenzaldehyde (1.0 g, 4.3 mmol), pinacol diboronate (1.3 g, 5.1 mmol), potassium acetate (1.3 g, 13 mmol) and [1,1'-bis (diphenylphosphino)ferrocene]palladium dichloride (50 mg, 0.07 mmol) was mixed with dry 1,4-dioxane (15 mL) solution, reacted at 100 °C for 4 h under nitrogen protection, cooled After reaching room temperature, the reaction solution was filtered with suction. After the filtrate was concentrated, water (30 mL) was added, extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 5/1) to obtain 752 mg of a pale yellow solid with a yield of 58%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.91 (s, 2H), 8.87 (d, J = 2.3 Hz, 2H), 8.56 (dd, J = 8.3, 2.3 Hz, 2H), 7.53 ( d, J = 8.3 Hz, 2H).

MS (ESI, pos.ion) m/z: 301.20 [M+H] ⁺ .

Step 2: Synthesis of compound 4,4'-dinitro-[1,1'-biphenyl]-2,2'-dimethanol

Compound 4,4'-dinitro-[1,1'-biphenyl]-2,2'-dicarbaldehyde (740 mg, 2.47 mmol) was dissolved in methanol (10 mL), cooled to 0 °C, added Sodium borohydride (203 mg, 5.37 mmol) was stirred at room temperature for 30 min to stop the reaction, water (25 mL) was added, extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the concentrated solution was subjected to silica gel column Chromatographic separation (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) gave 255 mg of pale yellow solid, yield 34%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.50 (s, 2H), 8.26 (dd, J = 8.3, 2.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 4.46 ( dd, J = 37.0, 12.7 Hz, 4H).

MS (ESI, pos.ion) m/z: 327.20 [M+Na] ⁺ .

Step 3: Synthesis of compound 3,9-dinitro-5,7-dihydrodibenzo[ c , e]oxazepine

4,4'-Dinitro-[1,1'-biphenyl]-2,2'-dimethanol (152 mg, 0.50 mmol), tributylphosphine (231 mg, 1.14 mmol) were dissolved in dry To the solution of tetrahydrofuran (5 mL), azodimethylamide (196 mg, 1.14 mmol) was slowly added under ice bath conditions, and the reaction was carried out at room temperature for 3 h, water (30 mL) was added, and ethyl acetate (15 mL × 3) was added. Extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 3/1) to obtain 106 mg of pale yellow solid, Yield 74%.

¹ H NMR (400 MHz, d ₆ -DMSO) δ (ppm): 8.51 (d, J = 2.2 Hz, 2H), 8.44 (dd, J = 8.5, 2.3 Hz, 2H), 7.99 (d, J = 8.5 Hz, 2H), 4.43 (s, 4H).

Step 4: Synthesis of compound 5,7-dihydrodibenzo[ c , e ]oxazepine-3,9-diamine

Compound 3,9-dinitro-5,7-dihydrodibenzo[ c , e ]oxazepine (100 mg, 0.35 mmol) was dissolved in methanol (10 mL), Pd/C (20 mg) was added , hydrogen was introduced into the reaction at room temperature for 5 h, the catalyst was removed by filtration, and the filtrate was concentrated to obtain 64 mg of a pale yellow solid with a yield of 81%.

¹ H NMR (400 MHz, d ₆ -DMSO) δ (ppm): 7.11 (d, J = 8.1 Hz, 2H), 6.65 (dd, J = 8.1, 2.2 Hz, 2H), 6.60 (d, J = 2.1 Hz, 2H), 5.11 (s, 4H), 4.08 (s, 4H).

MS (ESI, pos.ion) m/z: 227.20 [M+H] ⁺ .

Step 5: Compound 6-((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- methyl acyl amino) methyl) - N - (9- amino-5,7-dihydro-dibenzo synthesis [c, e] Zhuo oxa-3-yl) pyridin-acyl amine

The compound 6-((( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Amino)methyl)picolinic acid (100 mg, 0.20 mmol), 5,7-dihydrodibenzo[ c , e ]oxazepine-3,9-diamine (73 mg, 0.32 mmol), 1-ethyl Alkyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (251 mg, 1.31 mmol) and N -hydroxy-7-azabenzotriazole (54 mg, 0.40 mmol) were dissolved in In dichloromethane (5 mL), cooled to 0 °C, N , N -diisopropylethylamine (183 mg, 1.42 mmol) was added, the reaction was carried out at room temperature for 3 h, washed with water (15 mL), and washed with dichloromethane. Extraction (5 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain a pale Brown solid 44 mg, yield 31%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 10.74 (s, 1H), 8.98 (s, 1H), 8.24 (d, J = 7.4 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.04 (s, 1H), 7.86 - 7.90 (m, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.92 (s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.76 ( s, 1H), 6.61 (t, J _FH = 75.6 Hz, 1H), 4.86 - 4.90 (m, 1H), 4.62 - 4.80 (m, 2H), 4.39 (s, 2H), 4.30 (s, 2H), 3.93 - 3.97 (m, 1H), 3.88 (d, J = 6.7 Hz, 2H), 3.34 - 3.45 (m, 2H), 2.82 - 2.90 (m, 1H), 2.47 - 2.54 (m, 1H), 2.10 ( s, 3H), 1.68 - 1.79 (m, 1H), 0.63 - 0.66 (m, 2H), 0.34 - 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 712.50 [M+H] ⁺ .

Example 110: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((3-oxygen isoindol-5-yl)methyl)pyrrolidin-2-carboxamide

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120 mg, 0.32 mmol) and 6-(aminomethyl)isoindol-1-one (57 mg, 0.35 mmol) in dichloromethane (8 mL) and N , N -dimethylformamide (1 mL) , was added N -hydroxy-7-azabenzotriazole (88 mg, 0.65 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (186 mg, 0.97 mmol) and N , N -diisopropylethylamine (167 mg, 1.29 mmol), reacted at room temperature for 5 h, concentrated under reduced pressure to remove the solvent, added water (40 mL), extracted with ethyl acetate (25 mL × 2 ), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 97 mg of white solid, which was collected rate 58%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.42 (br.s, 1H), 7.84 (br.s, 1H), 7.43 – 7.60 (m, 2H), 7.25 – 7.33 (m, 1H) , 7.12 (d, J = 7.4 Hz, 1H), 6.83 – 6.95 (m, 2H), 6.61 (t, J _FH = 75.7 Hz, 1H), 4.91 – 5.08 (m, 1H), 4.62 – 4.78 (m, 1H), 4.10 – 4.26 (m, 1H), 3.90 – 4.03 (m, 2H), 3.88 (d, J = 4.7 Hz, 2H), 3.61 – 3.76 (m, 1H), 3.26 – 3.46 (m, 1H) , 2.55 – 2.73 (m, 1H), 2.29 – 2.44 (m, 1H), 2.16 (s, 3H), 1.21 – 1.36 (m, 1H), 0.59 – 0.69 (m, 2H), 0.31 – 0.42 (m, 2H).

MS (ESI, pos.ion) m/z: 514.15 [M+H] ⁺ .

Example 111: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((1-oxygen isoindol-5-yl)methyl)pyrrolidin-2-carboxamide

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100 mg, 0.27 mmol) and 5-(aminomethyl)isoindol-1-one (43 mg, 0.27 mmol) in dichloromethane (4 mL) and N , N -dimethylformamide (4 mL) , was added N -hydroxy-7-azabenzotriazole (73 mg, 0.54 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (156 mg, 0.81 mmol) and N , N -diisopropylethylamine (141 mg, 1.09 mmol), reacted at room temperature for 15 h, concentrated under reduced pressure to remove the solvent, added water (40 mL), extracted with ethyl acetate (25 mL × 2 ), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 57 mg of white solid, which was collected rate 41%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.01 (brs, 1H), 7.63 (br.s, 1H), 7.46 (d, J = 7.1 Hz, 1H), 7.34 (s, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.91 (s, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.61 (t, J _FH = 75.6 Hz, 1H), 4.65 – 4.80 (m, 2H), 4.16 – 4.33 (m, 3H), 3.87 – 3.98 (m, 1H), 3.87 (d, J = 6.5 Hz, 2H), 3.66 (d, J = 10.5 Hz, 1H), 3.28 – 3.43 (m, 1H), 2.56 – 2.69 (m, 1H), 2.34 – 2.48 (m, 1H), 2.15 (s, 3H), 1.21 – 1.36 (m, 1H), 0.59 – 0.69 (m, 2H), 0.31 – 0.42 (m, 2H).

MS (ESI, pos.ion) m/z: 514.25 [M+H] ⁺ .

Example 112: Compound (2 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) - N - (3,5- Dichloropyridin-4-yl)pyrrolidine-2-carboxamide

The first reaction: compound (2 R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Acid (200 mg, 0.54 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.3 mL, 2.0 mmol) and cyanuric fluoride (0.14 mL, 1.7 mmol) were added at -20°C, -20 The reaction was carried out at ℃ for 1 h, washed with ice and water (20 mL × 3), and then extracted with dichloromethane (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

The second reaction step: 3,5-dichloro-4-aminopyridine (108 mg, 0.66 mmol) was dissolved in dry N , N -dimethylformamide (7 mL), and 60% of the solution was added under ice bath. Sodium hydride (34 mg, 0.85 mmol) was reacted at room temperature for 1 h, the concentrated solution of the first reaction was added under an ice bath, and the reaction was stopped after 2 h at room temperature. N , N -dimethylformamide was removed under reduced pressure, water (10 mL) was added to the residue, extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: ethyl acetate (v) = 100%) to obtain 183 mg of a white solid with a yield of 65%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.48 (br.s, 1H), 8.54 (s, 2H), 7.15 (d, J = 8.1 Hz, 1H), 6.93 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.73 (t, J _FH = 75.5 Hz, 1H), 4.97 (t, J = 8.1 Hz, 1H), 4.01 – 4.06 (m, 1H), 3.90 (d, J = 6.9 Hz, 2H), 3.50 (t, J = 10.6 Hz, 1H), 3.36 – 3.45 (m, 1H), 2.81 – 2.89 (m, 1H), 2.58 – 2.65 (m, 1H), 2.24 (s , 3H), 1.27 – 1.36 (m, 1H), 0.65 – 0.69 (m, 2H), 0.36 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 514.20 [M+H] ⁺ .

Example 113: Compound ( 2R )-1-Acetyl- N- (3-(aminomethyl)phenyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethyl) Oxy)phenyl)pyrrolidine-2-carboxamide hydrochloride

Step 1: Compound 3-(( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-methyl Synthesis of tert-butyl acylamino)benzylcarbamate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (82 mg, 0.22 mmol), compound tert-butyl 3-aminobenzylcarbamate (96 mg, 0.43 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (143 mg, 0.74 mmol) and N -hydroxy-7-azabenzotriazole (72 mg, 0.53 mmol) were dissolved in dichloromethane (6 mL), to this solution was added dropwise N , N -diiso Propylethylamine (0.4 mL, 2.0 mmol), stirred at room temperature for 21 h, washed with water (50 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution Silica gel column chromatography was performed (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 112 mg of a white solid with a yield of 88%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 7.44-7.52 (m, 3H), 7.33-7.39 (m, 1H), 7.20-7.24 (m, 1H), 7.10-7.14 (m, 1H), 7.05-7.07 (m, 1H), 7.03 (t, J _FH = 74.9 Hz, 1H), 6.88-6.93 (m, 2H), 4.42-4.47 (m, 1H), 4.05-4.12 (m, 3H) ), 3.91 (d, J = 6.9 Hz, 2H), 3.44-3.52 (m, 2H), 2.60-2.65 (m, 1H), 2.02 (s, 3H), 1.95-2.00 (m, 1H), 1.40 ( s, 9H), 1.31-1.35 (m, 1H), 0.55-0.59 (m, 2H), 0.30-0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 596.25 [M+Na] ⁺ .

Step 2: Compound ( 2R )-1-Acetyl- N- (3-(aminomethyl)phenyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) Synthesis of phenyl) phenyl) pyrrolidine-2-carboxamide hydrochloride

The compound 3-(( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbamoylamino ) tert-butyl benzylcarbamate (112 mg, 0.2 mmol) was dissolved in dichloromethane (2 mL) solution, 4 mol/L HCl in ethyl acetate solution (3 mL) was added, stirred at room temperature for 30 min, removed solvent to obtain 53 mg of white solid with a yield of 96%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 10.36 (s, 1H), 7.77-7.79 (m, 1H), 7.59-7.64 (m, 1H), 7.33 (t, J = 8.0 Hz , 1H), 7.19-7.23 (m, 1H), 7.09-7.14 (m, 2H), 7.03 (t, J _FH = 74.9 Hz, 1H), 6.87-6.91 (m, 1H), 4.49-4.53 (m, 1H), 4.08-4.11 (m, 1H), 3.2 (s, 2H), 3.91 (d, J = 6.9 Hz, 2H), 3.45-3.54 (m, 2H), 2.60-2.70 (m, 1H), 2.02 (s, 3H), 1.87-1.98 (m, 1H), 1.23-1.27 (m, 1H), 0.51-0.61 (m, 2H), 0.29-0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 474.15 [M+H-HCl] ⁺ .

Example 114: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (3-(hydroxyl) Methyl)phenyl)pyrrolidine-2-carboxamide

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100 mg, 0.27 mmol), (3-aminophenyl)methanol (52 mg, 0.42 mmol) was dissolved in dry N , N -dimethylformamide (5 mL), N -hydroxy-7-azabenzone was added Triazole (73 mg, 0.54 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (259 mg, 1.35 mmol) and N , N were added in an ice bath -Diisopropylethylamine (174 mg, 1.35 mmol), react at room temperature for 12 h, add water (20 mL), stir for 5 min, extract with ethyl acetate (10 mL × 2), dry the organic phase with anhydrous sodium sulfate, reduce It was concentrated under pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 54/1) to obtain 85 mg of a light red solid with a yield of 62%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.64 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.92 (d, J =9.3 Hz, 1H), 6.91 (s, 1H), 6.85 (d, J =8.1 Hz, 1H), 6.61 (t, J _FH = 75.6 Hz, 1H), 4.75 (t, J = 8.1 Hz, 1H), 4.50 – 4.57 (m, 2H), 3.94 – 3.98 (m, 1H), 3.87 (d, J = 6.9 Hz, 2H) , 3.61 (t, J = 10.7 Hz, 1H), 3.31 – 3.40 (m, 1H), 2.87 (br.s, 1H), 2.46 – 2.63 (m, 2H), 2.17 (s, 3H), 1.25 – 1.36 (m, 1H), 0.62 – 0.67 (m, 2H), 0.33 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 475.15 [M+H] ⁺ .

Example 115: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (1-hydroxy- 1,3-Dihydrobenzo[c][1,2]oxaboran-5-yl)pyrrolidine-2-carboxamide

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100 mg, 0.27 mmol), 2-hydroxymethyl-5-aminophenylboronic acid half ester (48 mg, 0.32 mmol) was dissolved in dry N , N -dimethylformamide (5 mL) and N -hydroxy-7 - Azabenzotriazole (73 mg, 0.54 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (259 mg, 1.35 mmol) was added in an ice bath ) and N , N -diisopropylethylamine (174 mg, 1.35 mmol), react at room temperature for 5 h, add water (20 mL), stir for 5 min, extract with ethyl acetate (10 mL × 2), use anhydrous sodium sulfate The organic phase was dried, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 54/1) to obtain 35 mg of white solid, yield 25%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.78 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.06 – 7.12 ( m, 2H), 6.94 (d, J = 10.2 Hz, 1H), 6.74 (t, J _FH = 75.0 Hz, 1H), 5.06 (s, 2H), 4.56 – 4.62 (m, 1H), 4.10 – 4.15 ( m, 1H), 3.93 (d, J = 6.9 Hz, 2H), 3.68 (t, J = 10.5 Hz, 1H), 3.49 – 3.59 (m, 1H), 2.68 – 2.75 (m, 1H), 2.05 – 2.20 (m, 1H), 2.16 (s, 3H), 1.25 – 1.37 (m, 1H), 0.61 – 0.66 (m, 2H), 0.35 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 501.10 [M+H] ⁺ .

Example 116: Compound (2 R) -1- acetyl-4- (4- (difluoromethoxy) -3-isopropoxyphenyl) - N - (2- ethoxyphenyl) Pyrrolidine-2-carboxamide

Compound ( 2R )-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid (60 mg, 0.17 mmol), 2-Ethoxyaniline (69 mg, 0.50 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg, 0.83 mmol) and N -hydroxy-7 -Azabenzotriazole (45 mg, 0.33 mmol) was dissolved in dichloromethane (10 mL), and after cooling to 0 °C, N , N -diisopropylethylamine (155 mg, 1.20 mmol) was added , reacted at room temperature for 3 h, washed with water (10 mL × 3), stirred, separated the organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: dichloromethane/methanol ( v/v ) = 50/1) to obtain 71 mg of a light brown solid with a yield of 88%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.98 (s, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.94 – 6.99 (m, 2H), 6.85 – 6.91 (m, 2H), 6.55 (t, J _FH = 75.6 Hz, 1H), 4.79 (t, J = 8.1 Hz, 1H) , 4.52 – 4.64 (m, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.99 – 4.03 (m, 1H), 3.56 (t, J = 10.6 Hz, 1H), 3.34 – 3.43 (m, 1H) ), 2.64 (t, J = 8.7 Hz, 2H), 2.20 (s, 3H), 1.51 (t, J = 6.9 Hz, 3H), 1.37 (d, J = 6.0 Hz, 6H).

MS (ESI, pos.ion) m/z: 477.15 [M+H] ⁺ .

Example 117: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (1-oxo Isoindol-5-yl)pyrrolidine-2-carboxamide

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150 mg, 0.41 mmol), 5-aminoisoindol-1-one (72 mg, 0.49 mmol) and N -hydroxy-7-azabenzotriazole (110 mg, 0.81 mmol) were dissolved in dichloromethane (12 mL) ) and N , N -dimethylformamide (4 mL), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (233 mg, 1.22 mmol) and N , N -diisopropylethylamine (210 mg, 1.62 mmol), reacted at room temperature for 5 h, concentrated under reduced pressure to remove the solvent, added water (20 mL), extracted with ethyl acetate (10 mL × 2), the organic phase was It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 25/1) to obtain 126 mg of light brown solid, yield 62% .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 10.22 (s, 1H), 8.61 (s, 1H), 8.10 (s, 1H), 7.39 – 7.59 (m, 1H), 7.04 – 7.17 (m , 1H), 6.85 – 6.97 (m, 3H), 6.61 (t, J = 75.3 Hz, 1H), 4.68 – 4.87 (m, 1H), 4.15 – 4.36 (m, 2H), 3.95 – 4.09 (m, 1H) ), 3.78 – 3.93 (m, 2H), 3.62 – 3.77 (m, 1H), 3.32 – 3.56 (m, 1H), 2.56 – 2.78 (m, 1H), 2.29 – 2.46 (m, 1H), 2.24 (s , 3H), 1.26 – 1.37 (m, 1H), 0.57 – 0.71 (m, 2H), 0.27 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 500.10 [M+H] ⁺ .

Example 118: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (3-oxo Isoindol-5-yl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (203 mg, 0.55 mmol), 6-aminoisoindol-1-one (98 mg, 0.66 mmol) and N -hydroxy-7-azabenzotriazole (149 mg, 1.09 mmol) in anhydrous N , N -diazole Methylformamide (8 mL) was added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (310 mg, 1.62 mmol) and N , N -diisopropyl Ethylethylamine (283 mg, 2.19 mmol), reacted at room temperature for 10 h, concentrated under reduced pressure to remove the solvent, added water (30 mL), extracted with ethyl acetate (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate, reduced It was concentrated under pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 203 mg of white solid with a yield of 74%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 10.18 (br.s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.05 – 7.19 (m, 2H), 6.80 – 6.93 (m, 2H), 6.59 (t, J _FH = 75.8 Hz, 1H), 4.87 – 5.05 (m, 1H), 4.11 – 4.35 (m, 2H), 3.90 – 4.03 (m, 1H), 3.77 – 3.90 ( m, 2H), 3.56 – 3.70 (m, 1H), 3.31 – 3.50 (m, 1H), 2.70 – 2.87 (m, 1H), 2.26 – 2.43 (m, 1H), 2.11 – 2.20 (s, 3H), 1.23 – 1.32 (m, 1H), 0.55 – 0.68 (m, 2H), 0.26 – 0.33 (m, 2H).

MS (ESI, pos.ion) m/z: 500.45 [M+H] ⁺ .

Example 119: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (1-hydroxy- 1,3-Dihydrobenzo[ c ][1,2]oxaborolane-6-yl)pyrrolidine-2-carboxamide

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (200 mg, 0.54 mmol), 2-hydroxymethyl-6-aminophenylboronic acid half ester (96 mg, 0.65 mmol) and N -hydroxy-7-azabenzotriazole (147 mg, 1.08 mmol) were dissolved in anhydrous N , N -dimethylformamide (5 mL) was added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (312 mg, 1.63 mmol) and N , N - Diisopropylethylamine (279 mg, 2.16 mmol) was reacted at room temperature for 10 h, concentrated under reduced pressure to remove the solvent, added water (30 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with anhydrous sodium sulfate It was dried and concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 25/1) to obtain 166 mg of white solid with a yield of 61%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.45 (br.s, 1H), 7.70 (s, 2H), 7.03 – 7.16 (m, 2H), 6.94 (s, 1H), 6.75 – 6.87 (m, 1H), 6.61 (t, J _FH = 75.4 Hz, 1H), 4.77 – 5.00 (m, 1H), 4.88 (s, 2H), 3.85 – 4.00 (m, 1H), 3.83 – 3.90 (m, 2H), 3.61 – 3.76 (m, 1H), 3.30 – 3.50 (m, 1H), 2.56 – 2.74 (m, 1H), 2.38 – 2.52 (m, 1H), 2.13 (s, 3H), 1.23 – 1.32 ( m, 1H), 0.55 – 0.68 (m, 2H), 0.27 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 501.40 [M+H] ⁺ .

Example 120: Compound 6-(((( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine- 2-Carbonyl)oxy)methyl)nicotinic acid methyl ester

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (60 mg, 0.16 mmol), methyl 6-hydroxymethylnicotinate (32 mg, 0.19 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (155 mg, 0.81 mmol) ) and N -hydroxy-7-azabenzotriazole (44 mg, 0.32 mmol) were dissolved in dichloromethane (20 mL), cooled to 0 °C, added with N , N -diisopropylethylamine ( 126 mg, 0.97 mmol), react at room temperature for 20 h, add water to wash the organic phase (10 mL × 3), dry the organic phase with anhydrous sodium sulfate, remove the solvent, and separate the concentrated solution by silica gel column chromatography (eluent: dichloride Methane/methanol (v/v) = 30/1) to obtain 54 mg of light yellow viscous solid, yield 64%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 9.16 (s, 1H), 8.35 (dd, J = 8.2, 2.0 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.15 ( d, J = 8.7 Hz, 1H), 6.85 (s, 1H), 6.82 – 6.85 (m, 1H), 6.63 (t, J _FH = 75.5 Hz, 1H), 5.30 – 5.52 (m, 2H), 4.61 – 4.66 (m, 1H), 3.97 – 4.03 (m, 1H), 3.97 (s, 3H), 3.88 (d, J = 6.9 Hz, 2H), 3.63 – 3.68 (m, 1H), 3.43 – 3.52 (m, 1H), 2.72 – 2.79 (m, 1H), 2.09 – 2.22 (m, 1H), 2.15 (s, 3H), 1.27 – 1.36 (m, 1H), 0.65 – 0.70 (m, 2H), 0.36 – 0.40 ( m, 2H).

MS (ESI, pos.ion) m/z: 519.25 [M+H] ⁺ .

Example 121: Compound ( 2R )-2-ethoxybenzyl-1-acetoxy-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrole Alkane-2-carboxylate

The compound ( 2R )-1-acetyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (50 mg, 0.14 mmol), 2-ethoxybenzyl alcohol (61 mg, 0.40 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg, 0.68 mmol) and N -Hydroxy-7-azabenzotriazole (36 mg, 0.26 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, added with N , N -diisopropylethylamine (105 mg, 0.81 mmol), react at room temperature for 44 h, add water to wash the organic phase (20 mL × 2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the residue by silica gel column chromatography (eluent: petroleum ether/acetic acid) Ethyl ester (v/v) = 1/1) to obtain 33 mg of white viscous solid, yield 48%.

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.37 (d, J = 7.4 Hz, 1H), 7.28 – 7.32 (m, 1H), 7.10 – 7.14 (m, 1H), 6.94 – 6.97 (m , 1H), 6.87 – 6.91 (m, 1H), 6.83 (s, 1H), 6.67 – 6.81 (m, 1H), 6.62 (t, J _FH = 75.5 Hz, 1H), 5.23 – 5.37 (m, 2H) , 4.51 – 4.60 (m, 1H), 4.06 (q, J = 6.9 Hz, 2H), 3.94 – 3.97 (m, 1H), 3.87 (d, J = 6.9 Hz, 2H), 3.62 – 3.65 (m, 1H) ), 3.38 – 3.45 (m, 1H), 2.84 – 2.89 (m, 0.3H), 2.69 – 2.73 (m, 0.7 H), 2.14 (s, 2.3H), 1.98 (s, 0.7H), 2.02 – 2.11 (m, 1H), 1.41 (t, J = 6.9 Hz, 3H), 1.29 – 1.36 (m, 1H), 0.66 – 0.69 (m, 2H), 0.35 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 504.20 [M+H] ⁺ .

Example 122: Compound ( 2R )-(2-ethoxy-3-fluorobenzyl)-1-acetoxy-4-(3-(cyclopropylmethoxy)-4-(difluoromethyl) Oxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (50 mg, 0.14 mmol), 2-ethoxy-3-fluorobenzyl alcohol (46 mg, 0.27 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg, 0.68 mmol) and N -hydroxy-7-azabenzotriazole (36 mg, 0.26 mmol) were dissolved in dichloromethane (10 mL), cooled to 0 °C, and N , N -diisopropylethyl acetate was added. Amine (105 mg, 0.81 mmol), react at room temperature for 11 h, add water to wash the organic phase (20 mL × 2), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the residue by silica gel column chromatography (eluent). : petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 17 mg of white viscous solid, yield 24%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.01 – 7.18 (m, 4H), 6.83 (s, 1H), 6.82 (d, J = 7.1 Hz, 1H), 6.62 (t, J _FH = 75.5 Hz, 1H), 5.25 – 5.35 (m, 2H), 4.52 – 4.58 (m, 1H), 4.19 (q, J = 7.0 Hz, 2H), 3.94 – 3.98 (m, 1H), 3.87 (d, J = 7.0 Hz, 2H), 3.63 (t, J = 10.4 Hz, 1H), 3.37 – 3.47 (m, 1H), 2.65 – 2.72 (m, 1H), 2.14 (s, 2.4H), 1.97 (s, 0.6 H), 2.02 – 2.11 (m, 1H), 1.40 (t, J = 7.0 Hz, 3H), 1.27 – 1.36 (m, 1H), 0.66 – 0.70 (m, 2H), 0.36 – 0.39 (m, 2H) .

MS (ESI, pos.ion) m/z: 522.15 [M+H] ⁺ .

Example 123: Compound ( 2R )-(6-(isopropyl(methyl)aminocarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethyl) oxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-(isopropyl(methyl)carbamoyl)methyl picolinate

Compound 2,6-pyridinedicarboxylate monomethyl ester (500 mg, 2.76 mmol), N -isopropylmethylamine (264 mg, 2.64 mmol), 1-ethyl-(3-dimethylaminopropyl) ) carbodiimide hydrochloride (1.30 g, 6.80 mmol) and N -hydroxy-7-azabenzotriazole (751 mg, 5.52 mmol) were dissolved in dichloromethane (20 mL) and cooled to 0 °C, add N , N -diisopropylethylamine (1.10 g, 8.51 mmol), react at room temperature for 1 h, add water to wash (20 mL × 2) the organic phase, separate the organic phase, dry with anhydrous sodium sulfate, reduce It was concentrated under pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 622 mg of white solid with a yield of 95%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.17 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H) , 4.93 – 5.00 (m, 0.4H), 4.01 – 4.09 (m, 0.6H), 4.01 (s, 3H), 3.00 (s, 2H), 2.92 (s, 1H), 1.24 – 1.77 (m, 6H) .

MS (ESI, pos.ion) m/z: 237.25 [M+H] ⁺ .

Step 2: Synthesis of compound 6-(hydroxymethyl) -N -isopropyl- N-picolinamide

The compound 6-(isopropyl(methyl)carbamoyl)picolinate (680 mg, 2.39 mmol) was dissolved in dry tetrahydrofuran (5 mL), and lithium borohydride (96 mg, 4.51 mg) was added to the ice bath. mmol), the reaction was stopped after 30 min at room temperature, saturated aqueous sodium chloride solution (10 mL) was added, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to silica gel column Chromatographic separation (eluent: dichloromethane/methanol (v/v) = 100/1) gave 423 mg of a white solid with a yield of 78%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.17 (t, J = 7.7 Hz, 1H), 7.447.35 – 7.24 (m, 1H), 4.94 – 5.01 (m, 0.4H), 4.78 ( s, 3H), 2.99 (s, 1.8H), 2.83 (s, 1.2H), 1.20 – 1.26 (m, 6H).

MS (ESI, pos.ion) m/z: 209.20 [M+H] ⁺ .

Step 3: Compound ( 2R )-(6-(isopropyl(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy) Synthesis of yl)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (80 mg, 0.22 mmol), 6-(hydroxymethyl) -N -isopropyl- N -picoline amide (56 mg, 0.27 mmol), 1-ethyl-(3-dimethylaminopropyl)carboamide Diimine hydrochloride (207 mg, 1.08 mmol) and N -hydroxy-7-azabenzotriazole (58 mg, 0.43 mmol) were dissolved in dichloromethane (10 mL), cooled to 0 °C, N , N -diisopropylethylamine (141 mg, 1.09 mmol) was added, the reaction was carried out at room temperature for 6 h, water (15 mL) was added, the organic phase was washed with water (10 mL × 2), the organic phase was dried with anhydrous sodium sulfate, and the mixture was reduced It was concentrated under pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 54/1) to obtain 56 mg of light brown viscous solid with a yield of 46%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.80 (t, J = 7.7 Hz, 1H), 7.41 – 7.52 (m, 2H), 7.12 (d, J = 8.3 Hz, 1H), 6.82 ( s, 1H), 6.77 – 6.81 (m, 1H), 6.60 (t, J _FH = 75.5 Hz, 1H), 5.23 – 5.44 (m, 2H), 4.89 – 4.96 (m, 0.4H), 4.57 – 4.61 ( m, 1H), 3.92 – 4.00 (m, 0.6H), 3.92 – 3.97 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.63 (t, J = 10.4 Hz, 1H), 3.38 – 3.50 (m, 1H), 2.94 (s, 1.8H), 2.80 (s, 1.2H), 2.68 – 2.74 (m, 1H), 2.04 – 2.16 (m, 1H), 2.12 (s, 3H), 1.25 – 1.32 (m, 1H), 1.15 – 1.21 (m, 6H), 0.63 – 0.67(m, 2H), 0.34 – 0.37(m, 2H).

MS (ESI, pos.ion) m/z: 560.20 [M+H] ⁺ .

Example 124: Compound ( 2R )-(6-((2-(dimethylamino)ethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4- (3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-((2-(dimethylamino)ethyl)(methyl)carbamoyl)picolinate methyl ester

The compound 2,6-pyridinedicarboxylate monomethyl ester (500 mg, 2.76 mmol), N ¹ , N ¹ , N ² -trimethylethylenediamine (368 mg, 3.60 mmol), 1-ethyl-( 3-Dimethylaminopropyl)carbodiimide hydrochloride (1.30 g, 6.80 mmol) and N -hydroxy-7-azabenzotriazole (753 mg, 5.53 mmol) in dichloromethane (20 mL), cooled to 0 °C, added N , N -diisopropylethylamine (1.10 g, 8.51 mmol), reacted at room temperature for 8.5 h, added water (20 mL × 2) to wash the organic phase, and separated the organic phase , dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column separation (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 667 mg of light brown liquid with a yield of 91%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.17 (d, J = 7.7 Hz, 1H), 7.84 – 7.89 (m, 1H), 4.01 (s, 3H), 2.33 (s, 2H), 2.24 (s, 1H), 2.10 (s, 3H).

MS (ESI, pos.ion) m/z: 266.10 [M+H] ⁺ .

Step 2: Synthesis of compound N- (2-(dimethylamino)ethyl)-6-(hydroxymethyl) -N -methylpyridamide

Compound 6-((2-(dimethylamino)ethyl)(methyl)carbamoyl)picolinate (360 mg, 1.36 mmol) was dissolved in methanol (5 mL), and boron was added under ice bath Sodium hydride (410 mg, 10.8 mmol), the reaction was stopped after 3 h at room temperature, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column separation (eluent: dichloromethane/methanol (v/v) = 10/1) to obtain Colorless liquid 214 mg, 66% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.75 – 7.79 (m, 1H), 7.69 (d, J = 7.7, Hz, 0.6H), 7.50 (d, J = 7.6, Hz, 0.4H ), 7.31 (d, J = 7.9, Hz, 0.4H), 7.27 (d, J = 7.8, Hz, 0.6H), 4.47 (s, 0.8H), 4.72 (s, 1.2H), 3.69 (t, J = 6.8, Hz, 0.7H), 3.59 (t, J = 6.8, Hz, 1.3H), 3.14 (s, 2.2H), 3.05 (s, 0.8H), 2.73 (t, J = 6.8, Hz, 1.3H), 2.62 (t, J = 6.8, Hz, 0.7H), 2.33 (s, 2H), 2.19 (s, 4H)

MS (ESI, pos.ion) m/z: 238.20 [M+H] ⁺ .

Step 3: Compound ( 2R )-(6-((2-(dimethylamino)ethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-( Synthesis of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (60 mg, 0.16 mmol), N- (2-(dimethylamino)ethyl)-6-(hydroxymethyl) -N -picolinamide (45 mg, 0.19 mmol), 1-ethyl-(3-diamino) Methylaminopropyl)carbodiimide hydrochloride (207 mg, 1.08 mmol) and N -hydroxy-7-azabenzotriazole (44 mg, 0.32 mmol) were dissolved in dichloromethane (10 mL) ), cooled to 0°C, added N , N -diisopropylethylamine (83 mg, 0.64 mmol), reacted at room temperature for 9 h, added dichloromethane (15 mL), washed the organic phase with water (20 mL × 2 ), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 24/1) to obtain 47 mg of white viscous solid, Yield 49%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.78 – 7.83 (m, 1H), 7.50 – 7.57 (m, 2H), 7.12 (d, J = 8.7 Hz, 1H), 6.82 (s, 1H) ), 6.78 – 6.2 (m, 1H), 6.61 (t, J _FH = 75.5 Hz, 1H), 5.23 – 5.45 (m, 2H), 4.56 – 4.60 (m, 1H), 3.93 – 3.98 (m, 1H) , 3.86 (d, J = 6.9 Hz, 2H), 3.60 – 3.70 (m, 2H), 3.41 – 3.51 (m, 2H), 3.11 (s, 1.5H), 3.06 (s, 1.5H), 2.67 – 2.72 (m, 2H), 2.55 – 2.61 (m, 1H), 2.39 (s, 3H), 2.18 – 2.26 (m, 1H), 2.14 (s, 3H), 2.12 (s, 3H), 1.25 – 1.36 (m , 1H), 0.63 – 0.67 (m, 2H), 0.33 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 589.30 [M+H] ⁺ .

Example 125: Compound ( 2R )-(6-(methyl(propyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy) yl)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-(methyl(propyl)carbamoyl)-2-picolinate methyl ester

The compound pyridinedicarboxylate monomethyl ester (1.00 g, 5.5 mmol) was taken in a 50 mL single-neck flask, 35 mL of dichloromethane was added, stirred and dissolved, and N , N -methylpropylamine (0.70 g, 9.4 mmol) and N -hydroxy-7-azabenzotriazole (1.50 g, 11 mmol), followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide under ice bath Amine hydrochloride (3.23 g, 16.7 mmol) and N , N -diisopropylethylamine (5.73 g, 44 mmol), and finally stirred at room temperature for 7 h to stop the reaction, washed with water 3 times (30 mL × 3), It was dried over anhydrous Na ₂ SO ₄ , concentrated, and separated by silica gel column chromatography (gradient elution, eluent: petroleum ether/ethyl acetate (v/v) = 3:1, 2:1) to obtain pale yellow oil The compound was 1.21 g, and the yield was 92.8%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.17 (t, J = 8.1 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.85 (t, J = 8.1 Hz, 1H) ), 4.03 (s, 3H), 3.53 (t, J = 8.1 Hz, 1H), 3.41 (t, J = 8.1 Hz, 1H), 3.12 (d, J = 8.1 Hz, 3H), 1.80 – 1.70 (m , 2H), 1.01 (t, J = 8.1 Hz, 1H), 0.81 (t, J = 8.1 Hz, 2H).

MS (ESI, pos.ion) m/z: 237.20 [M+H] ⁺ .

Step 2: Synthesis of compound 6-hydroxymethyl- N , N -methylpropyl-2-picolinamide

Take the compound 6-(methyl(propyl)carbamoyl)-2-picolinate methyl ester (0.60 g, 2.5 mmol) in a 100 mL single-neck flask, add 10 mL of anhydrous tetrahydrofuran, and then add lithium borohydride under an ice bath (0.15 g, 6.9 mmol), stirred at room temperature for 5 h, stopped the reaction, added 20 mL of saturated sodium chloride solution under ice bath, extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, concentrated, and carried out a silica gel column Chromatographic separation (gradient elution, eluent: petroleum ether/ethyl acetate (v/v) = 1:1, 1:2) gave 290 mg of light cyan oil with a yield of 55%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.79 (t, J = 8.1 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H) ), 4.79 (s, 2H), 3.54 (t, J = 8.1 Hz, 1H), 3.28 (t, J = 8.1 Hz, 1H), 3.12 (s, 2H), 3.01 (s, 1H), 1.8-1.6 (m, 2H), 1.01 (t, J = 8.1 Hz, 1H), 0.80 (t, J = 8.1 Hz, 2H).

MS (ESI, pos.ion) m/z: 209.20 [M+H] ⁺ .

Step 3: Compound ( 2R )-(6-(methyl(propyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy) )-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Take compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120 mg, 0.32 mmol) in a 50 mL single-neck flask, add 10 mL of dichloromethane, stir, dissolve, and add 6-hydroxymethyl- N , N -methylpropyl-2-picolinamide (80 mg, 0.40 mmol) at room temperature mmol) and N -hydroxy-7-azabenzotriazole (80 mg, 0.60 mmol), followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide under ice bath Hydrochloride (210 mg, 1.10 mmol) and N , N -diisopropylethylamine (300 mg, 2.30 mmol), finally stirred at room temperature for 5.5 h to stop the reaction, washed with water 3 times (30 mL × 3), anhydrous dried over sodium sulfate, concentrated, and separated by silica gel column chromatography (gradient elution, eluent: dichloromethane/methanol (v/v) = 7:1, 6:1) to obtain 147.6 mg of pale yellow oil, Yield 81%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.87-7.76 (m , 1H), 7.58-7.50 (m , 2H), 7.18-7.10 (m, 1H), 6.88-6.83 (m, 2H) ), 6.67 (t, J _FH = 75.6 Hz, 1H), 5.47-5.42 (m, 1H), 5.34-5.28 (m, 2H), 4.65-4.56 (m, 1H), 3.98 (t, J = 8.0 Hz , 1H), 3.92-3.85 (m, 2H), 3.65(t, J = 8.1 Hz ,1H), 3.55-3.40 (m, 2H), 3.33-3.25 (m, 1H), 3.15-3.06 (m, 2H) ), 3.02-2.97 (m, 1H), 2.78-2.68 (m, 1H), 2.18-2.12 (m, 3H), 1.36-1.24 (m, 3H), 0.99 (t, J = 8.0 Hz, 1H), 0.79 (t, J = 8.0 Hz, 2H), 0.71-0.64 (m, 2H), 0.41-0.33 (m, 2H).

MS (ESI, pos.ion) m/z: 560.20 [M+H] ⁺ .

Example 126: Compound ( 2R )-(6-dimethylaminocarbamoyl)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-(dimethylaminocarboxy)-2-picolinate methyl ester

Take the compound pyridinedicarboxylate monomethyl ester (1.02 g, 5.63 mmol) in a 100 mL single-neck flask, add 40 mL of dichloromethane, stir, dissolve, and then add dimethylamine hydrochloride (2.49 g, 9.4 mmol) and N at room temperature. -Hydroxy-7-azabenzotriazole (1.50 g, 11 mmol), followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 3.23 g, 16.7 mmol) and N , N -diisopropylethylamine (5.73 g, 44 mmol), and finally stirred at room temperature for 5 h to stop the reaction, washed with water 3 times (30 mL × 3), dried over anhydrous sodium sulfate, Concentrated and separated by silica gel column chromatography (gradient elution, eluent: petroleum ether/ethyl acetate (v/v) = 2:1, 1:1) to obtain 1.05 g of pale yellow oil, yield 89.6 %.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.22-8.17 (m, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.90-7.85 (m, 1H), 4.03 (s, 3H), 3.19-3.13 (m, 5H), 3.02-2.88 (m, 1H).

MS (ESI, pos.ion) m/z: 209.10 [M+H] ⁺ .

Step 2: Synthesis of compound 6-hydroxymethyl- N , N -dimethyl-2-picolinamide

Take compound 6-(dimethylaminocarboxy)-2-picolinate methyl ester (0.52 g, 2.5 mmol) in a 25 mL single-neck flask, add 6 mL of anhydrous tetrahydrofuran, and then add lithium borohydride (0.11 g under ice bath) , 5.0 mmol), stirred at room temperature for 3 h, stopped the reaction, added 20 mL of saturated sodium chloride solution under ice bath, extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (gradient elution, eluent: DCM/MeOH (v/v) = 39:1, 6:1) to give a white solid 260 mg, yield 58%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.81 (t, J = 8.1 Hz, 1H), 7.55-7.50 (m, 1H), 7.37-7.30 (m, 1H), 4.80 (s, 2H), 3.17 (s, 3H), 3.07 (s, 1H).

MS (ESI, pos.ion) m/z: 181.25 [M+H] ⁺ .

Step 3: Compound ( 2R )-(6-(dimethyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Take compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120 mg, 0.32 mmol) in a 25 mL single-neck flask, add 11 mL of dichloromethane, stir, dissolve, and then add 6-hydroxymethyl- N , N -dimethyl-2-picolinamide (60 mg, 0.33 mmol at room temperature) ) and N -hydroxy-7-azabenzotriazole (90 mg, 0.65 mmol), followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide salt under ice bath acid (200 mg, 1.03 mmol) and N , N -diisopropylethylamine (400 mg, 3.03 mmol), and finally stirred at room temperature for 17 h to stop the reaction, washed with water 3 times (30 mL × 3), anhydrous sulfuric acid Dry over sodium, concentrate, and separate by silica gel column chromatography (gradient elution, eluent: dichloromethane/methanol (v/v) = 11:1, 10:1, 9:1) to give a pale yellow oil 78.9 mg, yield 44.6%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.84 (t, J = 8.1 Hz, 1H), 7.61-7.52 (m, 2H), 7.18-7.12 (m, 1H), 6.88-6.83 ( m, 2H), 6.63 (t, J _FH = 75.6 Hz, 1H), 5.47-5.42 (m, 1H), 5.34-5.28 (m, 2H), 4.65-4.56 (m, 1H), 4.02-3.96 (m , 1H), 3.92-3.85 (m, 2H), 3.68-3.62(m, 1H), 3.13 (s, 3H), 3.06 (s, 3H), 2.18-2.12 (m, 3H), 2.04-2.00 (m , 1H), 0.94-0.85 (m, 2H), 0.71-0.64 (m, 2H), 0.41-0.33 (m, 2H).

MS (ESI, pos.ion) m/z: 532.20 [M+H] ⁺ .

Example 127: Compound ( 2R )-(6-((cyanomethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropyl) methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 2-(methylamino)acetonitrile hydrochloride

Compound tert-butyl(cyanomethyl)(methyl)carbamate (300 mg, 0.066 mmol) was dissolved in dichloromethane (5 mL) solution, HCl in ethyl acetate (4 M, 8 mL) was added ), reacted at room temperature for 30 min, and concentrated under reduced pressure to obtain 176 mg of a light brown solid with a yield of 93%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 4.34 (s, 1H), 3.84 (s, 1H), 2.87 (s, 1.5H), 2.75 (s, 1.5H).

MS (ESI, pos.ion) m/z: 70.10 [M-HCl+H] ⁺ .

Step 2: Synthesis of compound 6-((cyanomethyl)(methyl)carbamoyl)picolinate methyl ester

Compound 2,6-pyridinedicarboxylate monomethyl ester (300 mg, 1.66 mmol), 2-(methylamino)acetonitrile hydrochloride (172 mg, 1.61 mmol), 1-ethyl-(3-dimethyl aminopropyl)carbodiimide hydrochloride (634 mg, 3.31 mmol) and N -hydroxy-7-azabenzotriazole (333 mg, 2.45 mmol) in dichloromethane (10 mL) , cooled to 0°C, added N , N -diisopropylethylamine (624 mg, 4.83 mmol), reacted at room temperature for 6 h, added water (20 mL × 2) to wash, separated the organic phase, and dried over anhydrous sodium sulfate , concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 121 mg of light brown liquid with a yield of 31%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.24 – 8.27 (m, 1H), 8.16 – 8.18 (m, 0.5H), 7.99 – 8.07 (m, 1.5H), 4.95 (s, 0.8H) ), 4.52 (s, 1.2H), 4.03 (s, 3H), 3.38 (s, 1.8H), 3.29 (s, 1.2H).

MS (ESI, pos.ion) m/z: 234.05 [M+H] ⁺ .

Step 3: Synthesis of Compound N- (cyanomethyl)-6-(hydroxymethyl) -N -picolinamide

Compound 6-((cyanomethyl)(methyl)carbamoyl)picolinate methyl ester (115 mg, 0.49 mmol) was dissolved in methanol (5 mL), and sodium borohydride (149 mg, 3.94 mmol), the reaction was stopped after 2.5 h at room temperature, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column separation (eluent: dichloromethane/methanol (v/v) = 15/1) to obtain 29 mg of a colorless liquid, which was collected rate of 28%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.86 – 7.91 (m, 1H), 7.81 (d, J = 7.5, Hz, 0.4H), 7.67 (d, J = 7.6, Hz, 0.6H) ), 7.44 (t, J = 8.6, Hz, 1H), 4.85 (d, J = 13.0, Hz, 2H), 4.55 (d, J = 8.5, Hz, 2H), 3.32 (br.s, 1H), 3.28 (s, 3H).

MS (ESI, pos.ion) m/z: 206.20 [M+H] ⁺ .

Step 4: Compound ( 2R )-(6-((cyanomethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropyl) Synthesis of Methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (50 mg, 0.14 mmol), N- (cyanomethyl)-6-(hydroxymethyl) -N -picolinamide (23 mg, 0.11 mmol), 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (107 mg, 0.56 mmol) and N -hydroxy-7-azabenzotriazole (32 mg, 0.24 mmol) were dissolved in dichloromethane (10 mL) and cooled to 0 ℃, N , N -diisopropylethylamine (78 mg, 0.60 mmol) was added, the reaction was carried out at room temperature for 14 h, water (15 mL) was added, stirred for 5 min, extracted with dichloromethane (10 mL × 2), and the mixture was washed with anhydrous sulfuric acid. The organic phase was dried over sodium, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 54/1) to obtain 16 mg of light brown viscous solid, yield 25% .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.82 – 7.94 (m, 1.5H), 7.58 – 7.70 (m, 1.5H), 7.12 (d, J = 7.6 Hz, 1H), 6.82 (s , 2H), 6.61 (t, J _FH = 75.5 Hz, 1H), 5.43 – 5.51 (m, 1H), 5.22 – 5.30 (m, 1H), 4.56 – 4.76 (m, 2H), 4.43 – 4.51 (m, 1H), 3.90 – 3.99 (m, 1H), 3.86 (d, J = 6.0 Hz, 2H), 3.60 – 3.65 (m, 1H), 3.37 – 3.51 (m, 1H), 3.24 (d, J = 11.4 Hz , 3H), 2.66 – 2.77 (m, 1H), 2.11 (s, 3H), 1.97 – 2.05 (m, 1H), 1.25 – 1.35 (m, 1H), 0.57 – 0.69 (m, 2H), 0.30 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 557.20 [M+H] ⁺ .

Example 128: Compound ( 2R )-(6-((2-methoxyethyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetoxy-4-(3 -(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-((2-methoxyethyl)carbamoyl)picolinate methyl ester

The compound 2,6-pyridinedicarboxylate monomethyl ester (500 mg, 2.76 mmol), 2-methoxyethylamine (402 mg, 5.35 mmol) was dissolved in dichloromethane (20 mL), N -hydroxyl was added -7-Azabenzotriazole (563 mg, 4.14 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.1 g) was added in an ice bath , 5.70 mmol) and N , N -diisopropylethylamine (890 mg, 6.89 mmol), reacted at room temperature for 5 h, the organic phase was washed with water (20 mL × 2), the organic phase was dried with anhydrous sodium sulfate, and the pressure was reduced. Concentrated, and the residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain 598 mg of white solid with a yield of 91%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.42 (br.s, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.01 (t, J = 7.8 Hz, 1H), 4.02 (s, 3H), 3.69 – 3.73 (m, 2H), 3.61 (t, J = 5.2 Hz, 2H), 3.41 (s, 3H).

MS (ESI, pos.ion) m/z: 239.10 [M-HCl+H] ⁺ .

Step 2: Synthesis of compound 6-((2-methoxyethyl)(methyl)carbamoyl)picolinate methyl ester

The compound 6-((2-methoxyethyl)carbamoyl)picolinate (585 mg, 2.46 mmol) was dissolved in anhydrous N , N -dimethylformamide (8 mL), in Add 60% sodium hydride (128 mg, 3.20 mmol) to an ice bath, react at room temperature for 1 h, add iodomethane (1.1 g, 7.70 mmol), react at 60 °C for 8 h, stop the reaction, remove the solvent under reduced pressure, add water (20 mL), the aqueous phase was extracted with ethyl acetate (10 mL × 3), 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: petroleum ether/ethyl acetate) (v/v) = 2/1) to obtain 199 mg of a light brown solid with a yield of 32%.

MS (ESI, pos.ion) m/z: 253.10 [M+H] ⁺ .

Step 3: Compound 6- (hydroxymethyl) - N - (2- methoxyethyl) - N - Synthesis of Amides methylpyridine

The compound 6-((2-methoxyethyl)(methyl)carbamoyl)picolinate (195 mg, 0.77 mmol) was dissolved in methanol (5 mL), and sodium borohydride was added to the ice bath (233 mg, 6.16 mmol), the reaction was stopped after 3.5 h at room temperature, concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 50/1) to obtain Colorless liquid 162 mg, yield 93%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.76 – 7.80 (m, 1H), 7.56 (d, J = 7.6 Hz, 0.6H), 7.50 (d, J = 7.6 Hz, 0.4H), 7.28 – 7.31 (m, 1H), 4.77 (s, 2H), 3.68 – 3.76 (m, 2H), 3.57 – 3.61 (m, 2H), 3.40 (s, 1.4H), 3.30 (s, 1.6H), 3.16 (s, 1.4H), 3.10 (s, 1.6H).

MS (ESI, pos.ion) m/z: 225.20 [M+H] ⁺ .

Step 4: Compound ( 2R )-(6-((2-methoxyethyl)(methyl)aminocarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3- Synthesis of (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (107 mg, 0.29 mmol), 6- (hydroxymethyl) - N - (2- methoxyethyl) - N - methylpyridine Amides (11029-1) (50 mg, 0.22 mmol) was dissolved in dichloromethane (10 mL), N -hydroxy-7-azabenzotriazole (61 mg, 0.45 mmol) was added, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide was added in an ice bath Amine hydrochloride (214 mg, 1.12 mmol) and N , N -diisopropylethylamine (144 mg, 1.11 mmol), react at room temperature for 6 h, add water (20 mL), stir for 5 min, and extract with dichloromethane ( 5 mL × 2), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 54/1) to obtain light brown The viscous solid was 78 mg, the yield was 60%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.81 (t, J = 7.6 Hz, 1H), 7.49 – 7.56 (m, 2H), 7.12 (d, J = 8.3 Hz, 1H), 6.82 ( s, 1H), 6.78 – 6.81 (m, 1H), 6.60 (t, J _FH = 75.5 Hz, 1H), 5.24 – 5.44 (m, 2H), 4.56 – 4.61 (m, 1H), 3.93 – 3.98 (m , 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.65 – 3.72 (m, 2H), 3.62 (t, J = 10.4 Hz, 1H), 3.50 – 3.58 (m, 2H), 3.39 – 3.49 ( m, 1H), 3.37 (s, 1.5H), 3.25 (s, 1.5H), 3.13 (s, 1.5H), 3.08 (s, 1.5H), 2.67 – 2.74 (m, 1H), 2.06 – 2.14 ( m, 1H), 2.12 (s, 3H), 1.25 – 1.36 (m, 1H), 0.62 – 0.67 (m, 2H), 0.33 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 576.20 [M+H] ⁺ .

Example 129: Compound ( 2R )-(6-(methyl(2,2,2-trifluoroethyl)carbamoyl)pyridin-2-yl)methyl 1-acetoxyl-4-( 3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-(methyl(2,2,2-trifluoroethyl)carbamoyl)picolinate methyl ester

The compound 2,6-pyridinedicarboxylate monomethyl ester (400 mg, 2.21 mmol), N -methyl-2,2,2-trifluoroethylamine hydrochloride (330 mg, 2.21 mmol) was dissolved in dichloro In methane (15 mL), N -hydroxy-7-azabenzotriazole (450 mg, 3.31 mmol) was added, and 1-ethyl-(3-dimethylaminopropyl)carbon was added in an ice bath Diimide hydrochloride (846 mg, 4.41 mmol) and N , N -diisopropylethylamine (999 mg, 7.73 mmol) were reacted at room temperature for 3.5 h, the organic phase was washed with water (20 mL × 2), The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain a colorless liquid 436 mg, yield 71%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.19 – 8.21 (m, 1H), 7.89 – 8.01 (m, 2H), 4.62 (q, J = 7.5, Hz, 1.2H), 4.21 ( q, J = 9.0, Hz, 0.8H), 4.01 (s, 3H), 3.30 (s, 1.3H), 3.25 (s, 1.7H).

MS (ESI, pos.ion) m/z: 277.20 [M +H] ⁺ .

Step 2: Synthesis of compound 6-(hydroxymethyl) -N -methyl N- (2,2,2-trifluoroethyl)-pyridinamide

The compound 6-(methyl(2,2,2-trifluoroethyl)carbamoyl)picolinate (430 mg, 1.56 mmol) was dissolved in methanol (5 mL), and hydroboration was added to the ice bath Sodium (294 mg, 7.78 mmol), the reaction was stopped after 1.5 h at room temperature, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column separation (eluent: dichloromethane/methanol (v/v) = 66/1) to obtain colorless Liquid 310 mg, yield 80%.

H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.80 – 7.85 (m, 1H), 7.55 – 7.64 (m, 1H), 7.37 (d, J = 8.8, Hz, 1H), 4.79 (d, J = 4.3, Hz, 2H), 4.32 (q, J = 8.6, Hz, 1H), 4.22 (q, J = 8.9, Hz, 1H), 3.24 (s, 1.5H), 3.19 (s, 1.5H).

MS (ESI, pos.ion) m/z: 249.20 [M+H] ⁺ .

Step 3: Compound ( 2R )-(6-(methyl(2,2,2-trifluoroethyl)aminocarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3 Synthesis of -(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (97 mg, 0.26 mmol), 6-(hydroxymethyl) -N -methyl- N- (2,2,2-trifluoroethyl)-pyridinamide (50 mg, 0.20 mmol) in dichloromethane (10 mL) ), N -hydroxy-7-azabenzotriazole (61 mg, 0.45 mmol) was added, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide was added in an ice bath Hydrochloride (214 mg, 1.12 mmol) and N , N -diisopropylethylamine (144 mg, 1.11 mmol), react at room temperature for 11 h, add water (20 mL), stir for 5 min, and extract with dichloromethane (5 mL × 2), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 54/1) to obtain a light brown viscous Solid 68 mg, yield 56%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.83 – 7.88 (m, 1H), 7.69 – 7.71 (m, 0.5H), 7.55 – 7.59 (m, 1.5H), 7.12 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 6.75 – 6.81 (m, 1H), 6.60 (t, J _FH = 75.5 Hz, 1H), 5.38 – 5.46 (m, 1H), 5.22 – 5.29 (m, 15H), 4.56 – 4.60 (m, 1H), 4.42 – 4.48 (m, 1H), 4.15 – 4.22 (m, 1H), 3.93 – 3.98 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H) , 3.63 (t, J = 10.4 Hz, 1H), 3.39 – 3.49 (m, 1H), 3.19 – 3.21 (m, 3H), 2.66 – 2.74 (m, 1H), 2.05 – 2.14 (m, 1H), 2.12 (s, 3H), 1.25 – 1.36 (m, 1H), 0.63 – 0.67 (m, 2H), 0.33 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 600.20 [M+H] ⁺ .

Example 130: Compound ( 2R )-(6-(morpholine-4-carbonyl)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-(morpholine-4-carbonyl)-2-picolinate methyl ester

Take the compound pyridinedicarboxylate monomethyl ester (1.04 g, 5.74 mmol) in a 50 mL single-necked flask, add 32 mL of dichloromethane, stir, dissolve, add morpholine (0.82 g, 9.4 mmol) and N -hydroxyl at room temperature -7-Azabenzotriazole (1.50 g, 10.8 mmol), followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.21 g) in an ice bath , 16.6 mmol) and N , N -diisopropylethylamine (5.78 g, 44.6 mmol), and finally stirred at room temperature for 3 h to stop the reaction, washed with water (30 mL × 3), dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel Column chromatography separation (gradient elution, eluent: petroleum ether/ethyl acetate (v/v) = 2:1, 1:1) gave 1.30 g of a white solid with a yield of 90.4%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.23-8.18 (m, 1H), 8.00 (t, J = 8.0 Hz, 1H), 7.96-7.91 (m, 1H), 4.03 (s, 3H), 3.85 (s, 4H), 3.75 (s, 4H).

MS (ESI, pos.ion) m/z: 251.10 [M+H] ⁺ .

Step 2: Synthesis of Compound (6-(hydroxymethyl)pyridin-2-yl)(morpholinyl)methanone

The compound 6-(morpholine-4-carbonyl)-2-picolinate methyl ester (0.71 g, 2.8 mmol) was taken into a 100 mL single-neck flask, 6 mL of anhydrous tetrahydrofuran was added, and then lithium borohydride (0.14 g, 6.4 mmol), stirred at room temperature for 5 h, stopped the reaction, added 20 mL of saturated NaCl solution in an ice bath, extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (gradient washing). For removal, eluent: dichloromethane/methanol (v/v) = 12:1, 11:1) to obtain 209 mg of white solid, yield 33%.

MS (ESI, pos.ion) m/z: 223.10 [M+H] ⁺ .

Step 3: Compound ( 2R )-(6-(morpholine-4-carbonyl)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropylmethoxy)-4- Synthesis of (difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Take compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (96.9 mg, 0.26 mmol) in a 25 mL single-neck flask, add 10 mL of dichloromethane, stir, dissolve, and then add 6-hydroxymethyl- N , N -methylpropyl-2-picolinamide (69.6 mg, 0.31 mmol) at room temperature mmol) and N -hydroxy-7-azabenzotriazole (77.1 mg, 0.56 mmol), followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide under ice bath Hydrochloride (159.0 mg, 0.82 mmol) and N , N -diisopropylethylamine (285.0 mg, 2.20 mmol), and finally stirred at room temperature for 6 h to stop the reaction, washed with water (30 mL × 3), anhydrous sodium sulfate dried, concentrated, and separated by silica gel column chromatography (gradient elution, eluent: dichloromethane/methanol (v/v) = 7:1, 6:1) to obtain pale yellow oil 78.1 mg, yield 51.9%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.89-7.82 (m, 1H), 7.62-7.58 (m, 1H), 7.57-7.54 (m, 1H), 7.18-7.14 (m, 1H) ), 6.88-6.83 (m, 2H), 6.64 (t, J _FH = 75.6 Hz, 1H), 5.47-5.42 (m, 1H), 5.28-5.24 (m, 1H), 4.64-4.58 (m, 1H) , 4.02-3.97 (m, 1H), 3.92-3.86 (m, 2H), 3.84-3.76(m, 4H), 3.72-3.67 (m, 2H), 3.65-3.60 (m, 2H), 2.76-2.71( m, 1H), 2.27-2.23 (m, 1H), 2.15 (s, 2H), 2.07-2.01 (m, 2H), 0.93-0.87 (m, 2H), 0.71-0.67 (m , 2H), 0.40- 0.35 (m, 2H).

MS (ESI, pos.ion) m/z: 574.60 [M+H] ⁺ .

Example 131: Compound ( 2R )-(6-(cyclohexyl(methyl)aminocarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy) yl)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-(cyclohexyl(methyl)carbamoyl)methyl picolinate

Compound 2,6-pyridinedicarboxylate monomethyl ester (500 mg, 2.76 mmol), N -methylcyclohexylamine (374 mg, 3.30 mmol), 1-ethyl-(3-dimethylaminopropyl) ) carbodiimide hydrochloride (1.30 g, 6.80 mmol) and N -hydroxy-7-azabenzotriazole (753 mg, 5.53 mmol) were dissolved in dichloromethane (20 mL) and cooled to 0 °C, N , N -diisopropylethylamine (1.5 mL, 8.10 mmol) was added, the reaction was carried out at room temperature for 17.5 h, the organic phase was washed with water (20 mL × 2), the organic phase was separated, dried over anhydrous sodium sulfate, and then reduced It was concentrated under pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 3/2) to obtain 754 mg of light brown liquid with a yield of 98%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.17 (t, J = 8.8 Hz, 1H), 7.93 – 7.98 (m, 1H), 7.78 – 7.85 (m, 1H), 4.50 – 4.58 (m , 0.4H), 4.02 (s, 1.2H), 4.01 (s, 1.8H), 3.63 – 3.70 (m, 0.6H), 3.03 (s, 1.8H), 2.93 (s, 1.2H), 1.78 – 1.97 (m, 4H), 1.46 – 1.49 (m, 4H), 1.09 – 1.17 (m, 2H).

MS (ESI, pos.ion) m/z: 277.20 [M+H] ⁺ .

Step 2: Synthesis of compound N -cyclohexyl-6-(hydroxymethyl) -N-picolinamide

The compound 6-(cyclohexyl(methyl)carbamoyl)picolinate (750 mg, 2.71 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium borohydride (117 mg, 5.50 mmol) was added under ice bath. , the reaction was stopped after 2.5 h at room temperature, saturated aqueous sodium chloride solution (30 mL) was added, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 632 mg of white solid, which was collected rate 93%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.97 (t, J = 7.8 Hz, 1H), 7.62 – 7.66 (m, 1H), 7.41 (d, J = 7.6 Hz, 1H), 4.72 – 4.73 (m, 2H), 3.36 – 3.42 (m, 0.6H), 3.01 (s, 1.8H), 2.82 (s, 1.2H), 2.58 – 2.65 (m, 0.4H), 1.76 – 1.93 (m, 4H), 1.42 – 1.67 (m, 4H), 1.06 – 1.21 (m, 2H).

MS (ESI, pos.ion) m/z: 249.30 [M+H] ⁺ .

Step 3: Compound ( 2R )-(6-(cyclohexyl(methyl)carbamoyl)pyridin-2-yl)methyl-1-acetyl-4-(3-(cyclopropylmethoxy) Synthesis of yl)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (80 mg, 0.22 mmol), N -cyclohexyl-6-(hydroxymethyl) -N -picoline amide (53 mg, 0.21 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Imine hydrochloride (207 mg, 1.08 mmol) and N -hydroxy-7-azabenzotriazole (60 mg, 0.44 mmol) were dissolved in dichloromethane (8 mL), cooled to 0 °C, added N , N -diisopropylethylamine (167 mg, 1.29 mmol), react at room temperature for 13 h, add dichloromethane (15 mL), wash the organic phase with water (20 mL × 2), and dry the organic phase with anhydrous sodium sulfate , concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 50/1) to obtain 83 mg of white viscous solid with a yield of 64%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.80 – 7.85 (m, 1H), 7.45 – 7.55 (m, 2H), 7.15 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H) ), 6.80 – 6.84 (m, 1H), 6.63 (t, J _FH = 75.5 Hz, 1H), 5.25 – 5.46 (m, 2H), 4.59 – 4.64 (m, 1H), 3.95 – 4.01 (m, 1H) , 3.89 (d, J = 6.7 Hz, 2H), 3.63 – 3.68 (m, 1H), 3.40 – 3.54 (m, 2H), 3.00 (s, 1.8H), 2.83 (s, 1.2H), .70 – 2.77 (m, 1H), 2.10 – 2.17 (m, 1H), 2.15 (s, 3H), 1.73 – 1.87 (m, 4H), 1.46 – 1.58 (m, 4H), 1.28 – 1.31 (m, 1H), 1.05 – 1.16 (m, 2H), 0.65 – 0.69 (m, 2H), 0.36 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 600.30 [M+H] ⁺ .

Example 132: Compound ( 2R )-(6-(methyl(p-tolyl)aminocarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethyl) oxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-(methyl(p-tolyl)carbamoyl)picolinate methyl ester

Compound 2,6-pyridinedicarboxylate monomethyl ester (500 mg, 2.76 mmol), N -methyl-4-methylaniline (402 mg, 3.32 mmol), 1-ethyl-(3-dimethylaniline) Aminopropyl)carbodiimide hydrochloride (1.30 g, 6.80 mmol) and N -hydroxy-7-azabenzotriazole (753 mg, 5.53 mmol) were dissolved in dichloromethane (20 mL) , cooled to 0 °C, N , N -diisopropylethylamine (1.10 g, 8.51 mmol) was added, the reaction was carried out at room temperature for 17 h, and the organic phase was washed with water (20 mL × 2), and the organic phase was separated and washed with anhydrous sodium sulfate. It was dried, concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column separation (eluent: petroleum ether/ethyl acetate (v/v) = 3/2) to obtain 761 mg of light brown liquid with a yield of 97%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.97 (d, J = 7.5 Hz, 1H), 7.73 (t, J = 8.8 Hz, 1H), 7.57 (d, J = 7.4 Hz, 1H) , 6.96 – 7.01 (m, 4H), 3.92 (s, 3H), 3.51 (s, 3H), 2.26 (s, 3H).

MS (ESI, pos.ion) m/z: 285.20 [M+H] ⁺ .

Step 2: Synthesis of compound 6-(hydroxymethyl) -N -methyl- N- (p-tolyl)pyridinamide

The compound 6-(methyl(p-tolyl)carbamoyl)picolinate (680 mg, 2.39 mmol) was dissolved in methanol (8 mL), and sodium borohydride (271 mg, 7.16 mmol) was added to the ice bath. ), the reaction was stopped after 3 h at room temperature, saturated aqueous sodium chloride solution (30 mL) was added, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to a silica gel column layer. Separation (eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain 171 mg of white solid, yield 27%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.58 – 7.67 (m, 2H), 6.97 – 7.07 (m, 5H), 4.49 (s, 2H), 3.52 (s, 3H), 2.85 ( br.s, 1H), 2.30 (s, 3H).

MS (ESI, pos.ion) m/z: 257.20 [M+H] ⁺ .

Step 3: Compound ( 2R )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy) Synthesis of yl)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (80 mg, 0.22 mmol), 6-(hydroxymethyl) -N -methyl- N- (p-tolyl)pyridinamide (52 mg, 0.22 mmol), 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (207 mg, 1.08 mmol) and N -hydroxy-7-azabenzotriazole (58 mg, 0.43 mmol) were dissolved in dichloromethane (10 mL) and cooled to 0 ℃, add N , N -diisopropylethylamine (141 mg, 1.09 mmol), react at room temperature for 9 h, add dichloromethane (15 mL), wash the organic phase with water (20 mL × 2), wash with anhydrous sodium sulfate The organic phase was dried, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/2) to obtain 87 mg of white viscous solid with a yield of 65%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.54 – 7.66 (m, 1H), 7.31 – 7.40 (m, 1H), 7.22 – 7.28 (m, 1H), 7.14 (d, J = 8.3 Hz , 1H), 6.93 – 6.99 (m, 4H), 6.84 (s, 1H), 6.82 (d, J = 3.9 Hz, 1H), 6.62 (t, J _FH = 75.5 Hz, 1H), 5.04 – 5.24 (m , 2H), 4.55 – 4.59 (m, 1H), 3.95 – 3.99 (m, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.63 (t, J = 10.5 Hz, 1H), 3.39 – 3.52 ( m, 1H), 3.48 (s, 3H), 2.68 – 2.74 (m, 1H), 2.27 (s, 3H), 2.13 (s, 3H), 2.03 – 2.11 (m, 1H), 1.27 – 1.35 (m, 1H), 0.65 – 0.69 (m, 2H), 0.36 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 608.50 [M+H] ⁺ .

Example 133: Compound ( 2R )-(6-((4-fluorophenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-( Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-hydroxymethylpyridine-2-carboxylate methyl ester

Compound 2,6-pyridinedicarboxylate monomethyl ester (1.0 g, 5.5 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) solution, added N , N -carbonyldiimidazole (1.1 g, 6.8 mmol), heated at 50 °C The reaction was stopped after 1 h, cooled to room temperature, sodium borohydride (320 mg, 8.4 mmol) was added, the reaction was carried out at room temperature for 2.5 h, water (25 mL) was added to quench the reaction, and extracted with ethyl acetate (30 mL × 6) , dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain 704 mg of a colorless liquid with a yield of 76%.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.00 (t, J = 7.7 Hz, 1H), 7.94 (t, J = 8.3 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 4.62 (s, 2H), 3.88 (s, 3H).

MS (ESI, pos.ion) m/z: 168.20 [M+H] ⁺ .

Step 2: Synthesis of compound 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinate methyl ester

The compound 6-hydroxymethylpyridine-2-carboxylic acid methyl ester (700 mg, 4.19 mmol) was dissolved in dichloromethane (10 mL) solution, triethylamine (639 mg, 6.31 mmol) was added, and the ice bath was added tert-Butyldimethylsilyl trifluoromethanesulfonate (1.3 g, 4.90 mmol) was reacted at room temperature for 3 h, the reaction was stopped, the organic phase was washed with water (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and carried out Silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1) gave 744 mg of a colorless liquid with a yield of 63%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.02 (d, J = 7.7 Hz, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H) , 4.96 (s, 2H), 4.02 (s, 3H), 0.98 (s, 9H), 0.14 (s, 6H).

MS (ESI, pos.ion) m/z: 282.20 [M+H] ⁺ .

Step 3: Synthesis of compound 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinic acid

The compound 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinate (740 mg, 2.63 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL) , Lithium hydroxide monohydrate (220 mg, 5.24 mmol) was added, the reaction was stopped after 45 min at 60 °C, diluted hydrochloric acid was added to adjust the pH of the solution to 6, extracted with ethyl acetate (20 mL × 3), and the organic phase was washed with anhydrous sodium sulfate. After drying, the solvent was removed to obtain 232 mg of a white solid with a yield of 33%.

MS (ESI, pos.ion) m/z: 268.20 [M+H] ⁺ .

Step 4: Compound 6 - (((tert-butyldimethyl silicon based) oxy) methyl) - N - (4- fluorophenyl) - N - acyl amine-methylpyridine

Compound 6-(((tert-butyldimethylsilyl)oxy)methyl)picolinic acid (200 mg, 0.75 mmol), 4-fluoro- N -methylaniline (134 mg, 0.99 mmol), 1 -Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (716 mg, 3.74 mmol) and N -hydroxy-7-azabenzotriazole (203 mg, 1.49 mmol) were dissolved In dichloromethane (10 mL), cooled to 0 °C, N , N -diisopropylethylamine (280 mg, 2.17 mmol) was added, the reaction was carried out at room temperature for 10 h, dichloromethane (15 mL) was added, The organic phase was washed with water (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1 ) to obtain 113 mg of light brown liquid with a yield of 44%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.60 – 7.69 (m, 1H), 7.34 – 7.40 (m, 2H), 6.99 – 7.12 (m, 2H), 6.86 – 6.95 (m, 2H) , 4.55 (s, 2H), 3.50 (s, 3H), 0.94 (s, 9H), 0.07 (s, 6H).

MS (ESI, pos.ion) m/z: 375.20 [M+H] ⁺ .

Step 5: Synthesis of compound N- (4-fluorophenyl)-6-(hydroxymethyl) -N -picoline pyridinamide

Compound 6 - (((tert-butyldimethyl silicon based) oxy) methyl) - N - (4- fluorophenyl) - N - Amides methylpyridine (107 mg, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL), add 3 mol/L tetrabutylammonium fluoride solution in tetrahydrofuran (1.5 mL), react at room temperature for 2 h, add saturated sodium chloride (5 mL), extract with ethyl acetate (15 mL × 2 ), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: ethyl acetate (v) = 100%) to obtain 68 mg of white solid with a yield of 91%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.67 – 7.71 (m, 1H), 7.59 – 7.61 (m, 1H), 7.04 – 7.13 (m, 3H), 6.94 – 6.98 (m, 2H) , 4.52 (s, 2H), 3.52 (s, 3H).

MS (ESI, pos.ion) m/z: 261.20 [M+H] ⁺ .

Step 6: Compound ( 2R )-(6-((4-fluorophenyl)(methyl)aminocarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclo Synthesis of Propylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (51 mg, 0.14 mmol), N- (4-fluorophenyl)-6-(hydroxymethyl) -N -picolinamide (35 mg, 0.14 mmol), 1-ethyl-(3-dimethylaminopropyl) yl)carbodiimide hydrochloride (260 mg, 1.36 mmol) and N -hydroxy-7-azabenzotriazole (55 mg, 0.40 mmol) were dissolved in dichloromethane (10 mL) and cooled to 0 °C, N , N -diisopropylethylamine (174 mg, 1.35 mmol) was added, the reaction was carried out at room temperature for 10 h, dichloromethane (15 mL) was added, and the organic phase was washed with water (20 mL × 2). It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 30/1) to obtain 59 mg of white viscous solid, yield 70% .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.59 – 7.68 (m, 1H), 7.31 – 7.43 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.97 – 7.05 (m , 2H), 6.84 – 6.93 (m, 2H), 6.82 (s, 1H), 6.77 – 6.81 (m, 1H), 6.60 (t, J _FH = 75.5 Hz, 1H), 5.10 – 5.21 (m, 1H) , 4.90 – 5.02 (m, 1H), 4.51 – 4.55 (m, 1H), 3.92 – 3.97 (m, 1H), 3.86 (d, J = 6.8 Hz, 2H), 3.61 (t, J = 10.4 Hz, 1H) ), 3.46 (s, 3H), 3.39 – 3.50 (m, 1H), 2.64 – 2.71 (m, 1H), 2.11 (s, 3H), 2.01 – 2.11 (m, 1H), 1.25 – 1.34 (m, 1H) ), 0.62 – 0.67(m, 2H), 0.34 – 0.38(m, 2H).

MS (ESI, pos.ion) m/z: 612.20 [M+H] ⁺ .

Example 134: Compound ( 2R )-(3-(aminocarboxy)benzyl)1-acetoxy-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) )Phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150 mg, 0.41 mmol), 3-(hydroxymethyl)benzamide (74 mg, 0.49 mmol) and N -hydroxy-7-azabenzotriazole (111 mg, 0.82 mmol) were dissolved in dichloromethane (8 mL) and N , N -dimethylformamide (1 mL), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (234 mg, 1.22 mmol) and N , N -diisopropylethylamine (210 mg, 1.62 mmol), reacted at room temperature for 5 h, concentrated under reduced pressure to remove the solvent, added water (30 mL), extracted with ethyl acetate (10 mL × 2), organic The phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 35/1) to obtain 137 mg of white solid, yield 67% .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.98 (s, 1H), 7.89 – 7.95 (m, 1H), 7.35 – 7.47 (m, 2H), 7.12 (d, J = 7.3 Hz, 1H ), 6.78 – 6.89 (m, 2H), 6.60 (t, J _FH = 75.4 Hz, 1H), 5.55 (d, J = 13.0 Hz, 1H), 5.12 (d, J = 13.1 Hz, 1H), 4.54 – 4.63 (m, 1H), 3.92 – 3.99 (m, 1H), 3.86 (d, J = 6.0 Hz, 2H), 3.60 – 3.66 (m, 1H), 3.39 – 3.50 (m, 1H), 2.65 – 2.76 ( m, 1H), 2.05 – 2.17 (m, 1H), 2.10 (s, 3H), 1.21 – 1.32 (m, 1H), 0.56 – 0.69 (m, 2H), 0.26 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 503.15 [M+H] ⁺ .

Example 135: Compound ( 2R )-(6-(aminocarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150 mg, 0.41 mmol), 6-(hydroxymethyl)pyridamide (74 mg, 0.49 mmol) and N -hydroxy-7-azabenzotriazole (110 mg, 0.81 mmol) were dissolved in dichloromethane (8 mL) ) and N , N -dimethylformamide (1 mL), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (233 mg, 1.22 mmol) and N , N -diisopropylethylamine (209 mg, 1.62 mmol), reacted at room temperature for 5 h, concentrated under reduced pressure to remove the solvent, added water (30 mL), extracted with ethyl acetate (10 mL × 2), the organic phase was It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 35/1) to obtain 112 mg of white solid with a yield of 55%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.11 (d, J = 7.3 Hz, 1H), 8.07 (br.s, 1H), 7.85 – 7.89 (m, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.76 – 6.88 (m, 2H), 6.60 (t, J _FH = 75.5 Hz, 1H), 5.48 (d, J = 13.7 Hz, 1H), 5.22 (d, J = 13.7 Hz, 1H), 4.59 – 4.63 (m, 1H), 3.95 – 3.99 (m, 1H), 3.85 (d, J = 6.6 Hz, 2H), 3.61 – 3.66 (m , 1H), 3.39 – 3.50 (m, 1H), 2.67 – 2.77 (m, 1H), 2.05 – 2.17 (m, 1H), 2.12 (s, 3H), 1.21 – 1.32 (m, 1H), 0.59 – 0.68 (m, 2H), 0.28 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 504.10 [M+H] ⁺ .

Example 136: Compound ( 2R )-(3-oxoisoindol-5-yl)methyl 1-acetoxy-4-(3-(cyclopropylmethoxy)-4-(difluoro) Methoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150 mg, 0.41 mmol), 6-(hydroxymethyl)isoindol-1-one (99 mg, 0.61 mmol) and N -hydroxy-7-azabenzotriazole (110 mg, 0.81 mmol) in dichloro To methane (8 mL) and N , N -dimethylformamide (1 mL), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (233 mg, 1.22 mmol) and N , N -diisopropylethylamine (209 mg, 1.62 mmol), reacted at room temperature for 6 h, concentrated under reduced pressure to remove the solvent, added water (30 mL), extracted with ethyl acetate (10 mL × 2 ), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 35/1) to obtain 19 mg of white solid, which was collected rate of 9%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.85 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.25 – 7.21 ( m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.59 (t, J _FH = 75.5 Hz, 1H), 5.29 (s, 2H), 4.52 – 4.56 (m, 1H), 4.45 (s, 2H), 3.92 – 3.96 (m, 1H), 3.85 (d, J = 6.9 Hz, 2H), 3.59 – 3.65 (m, 1H) ), 3.37 – 3.46 (m, 1H), 2.64 – 2.71 (m, 1H), 2.12 (s, 3H), 1.99 – 2.08 (m, 1H), 1.25 – 1.33 (m, 1H), 0.61 – 0.66 (m , 2H), 0.32 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 515.20 [M+H] ⁺ .

Example 137: Compound ( 2R )-(1-oxoisoindol-5-yl)methyl 1-acetoxy-4-(3-(cyclopropylmethoxy)-4-(difluoro) Methoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (200 mg, 0.54 mmol) and 5-(hydroxymethyl)isoindol-1-one (220 mg, 1.35 mmol) were dissolved in N , N -dimethylformamide (5 mL) and N -hydroxy-7- Azabenzotriazole (147 mg, 1.08 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (312 mg, 1.63 mmol) and N , N- Diisopropylethylamine (201 mg, 1.56 mmol) was reacted at room temperature for 11 h, concentrated under reduced pressure to remove the solvent, added water (30 mL), extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with anhydrous sodium sulfate It was dried, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 25/1) to obtain 129 mg of white solid, yield 46%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.86 (d, J = 6.8 Hz, 1H), 7.52 (s, 1H), 7.43 – 7.47 (m, 1H), 7.11 (d, J = 7.7 Hz, 1H), 6.81 (s, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.60 (t, J _FH = 75.6 Hz, 1H), 5.24 – 5.36 (m, 2H), 4.50 – 4.59 ( m, 1H), 4.47 (s, 2H), 3.90 – 3.99 (m, 1H), 3.85 (d, J = 6.5 Hz, 2H), 3.57 – 3.66 (m, 1H), 3.37 – 3.50 (m, 1H) , 2.63 – 2.74 (m, 1H), 2.13 (s, 3H), 2.00 – 2.08 (m, 1H), 1.25 – 1.33 (m, 1H), 0.60 – 0.69 (m, 2H), 0.30 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 515.10 [M+H] ⁺ .

Example 138: Compound ( 2R )-(1-hydroxy-1,3-dihydrobenzo[ c ][1,2]oxaboran-5-yl)1-acetyl-4-(3- (Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100 mg, 0.27 mmol), 2-hydroxymethyl-5-hydroxyphenylboronic acid half ester (48 mg, 0.32 mmol) was dissolved in dry N , N -dimethylformamide (5 mL) and N -hydroxy-7 - Azabenzotriazole (73 mg, 0.54 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (259 mg, 1.35 mmol) was added in an ice bath ) and N , N -diisopropylethylamine (174 mg, 1.35 mmol), react at room temperature for 5 h, add water (20 mL), stir for 5 min, extract with ethyl acetate (10 mL × 2), use anhydrous sodium sulfate The organic phase was dried, concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 54/1) to obtain 42 mg of white solid with a yield of 31%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.70 (s, 1H), 7.18 (s, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.09 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.76 (t, J _FH = 75.6 Hz, 1H), 5.08 (s, 2H), 4.68 – 4.71 (m, 1H) , 4.15 – 4.18 (m, 1H), 3.94 (d, J = 6.7 Hz, 2H), 3.71 (t, J = 10.2 Hz, 1H), 3.61 – 3.68 (m, 1H), 2.86 – 2.90 (m, 1H) ), 2.22 – 2.28 (m, 1H), 2.19 (s, 3H), 1.31 – 1.38 (m, 1H), 0.61 – 0.66 (m, 2H), 0.37 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 502.10 [M+H] ⁺ .

Example 139: Compound ( 2R )-(3-oxoisoindol-5-yl)1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) yl)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (200 mg, 0.54 mmol), 5-hydroxyisoindol-1-one (96 mg, 0.64 mmol) and N -hydroxy-7-azabenzotriazole (149 mg, 1.09 mmol) were dissolved in dichloromethane (12 mL) ) and N , N -dimethylformamide (4 mL), add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (313 mg, 1.63 mmol) and N , N -diisopropylethylamine (282 mg, 2.18 mmol), reacted at room temperature for 5 h, concentrated under reduced pressure to remove the solvent, added water (40 mL), extracted with ethyl acetate (15 mL × 2), the organic phase was It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 35/1) to obtain 163 mg of white solid with a yield of 60%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.60 (s, 1H), 7.43 – 7.48 (m, 2H), 7.24 – 7.34 (m, 1H), 7.16 (d, J = 6.0 Hz, 1H) ), 6.80 – 6.94 (m, 2H), 6.64 (t, J = 75.3 Hz, 1H), 4.64 – 4.80 (m, 1H), 4.46 (s, 2H), 3.96 – 4.09 (m, 1H), 3.89 ( d, J = 4.6 Hz, 2H), 3.63 – 3.74 (m, 1H), 3.46 – 3.60 (m, 1H), 2.77 – 2.92 (m, 1H), 2.17 – 2.32 (m, 1H), 2.16 (s, 3H), 1.26 – 1.38 (m, 1H), 0.59 – 0.71 (m, 2H), 0.31 – 0.44 (m, 2H).

MS (ESI, pos.ion) m/z: 501.10 [M+H] ⁺ .

Example 140: Compound ( 2R )-(2-methyl-1-oxoisoindol-5-yl)1-acetyl-4-(3-(cyclopropylmethoxy)-4- (difluoromethoxy)phenyl)pyrrolidine-2-carboxylate; and

和實施例141：

Example 141: Compound ( 2R )-(2,3-Dimethyl-1-oxoisoindol-5-yl)1-acetyl-4-(3-(cyclopropylmethoxy) -4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate Example 140:

and Example 141:

Step 1: Synthesis of compound 5-(benzyloxy)isoindol-1-one

5-Hydroxyisoindol-1-one (400 mg, 2.68 mmol) and potassium carbonate (741 mg, 5.36 mmol) were mixed, anhydrous N , N -dimethylformamide (5 mL) solution and benzyl bromide were added (688 mg, 4.02 mmol), reacted at 80 °C for 4 h, cooled to room temperature, added water (60 mL) to precipitate a white solid, suction filtered, and the filter cake was dried to obtain 536 mg of a white solid with a yield of 84%.

¹ H NMR (400 MHz, d ₆ -DMSO) δ (ppm): 8.32 (br.s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.46 – 7.47 (m, 2H), 7.38 – 7.42 (m, 2H), 7.32 – 7.36 (m, 1H), 7.21 (s, 1H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 5.18 (s, 2H), 4.31 (s, 2H).

MS (ESI, pos.ion) m/z: 240.10 [M+H] ⁺ .

Step 2: Synthesis of Compounds 5-(benzyloxy)-2-methylisoindol-1-one and 5-(benzyloxy)-2,3-dimethylisoindol-1-one

5-(benzyloxy)isoindol-1-one (400 mg, 1.67 mmol) was dissolved in anhydrous dimethyl sulfoxide (5 mL) solution, cooled in an ice bath, and 60% sodium hydride (133 mL) was added. mg, 3.33 mmol) for 30 min, then iodomethane (475 mg, 3.33 mmol) was added to react for 4 h, water (60 mL) was added to quench the reaction, extracted with dichloromethane (10 mL × 2), and the organic phase was combined with anhydrous sulfuric acid After drying over sodium, the solvent was removed, and the concentrated solution was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 40/1) to obtain 414 mg of the mixture as a pale yellow liquid, with a total yield of 95%.

Step 3: Synthesis of Compounds 5-hydroxy-2-methylisoindol-1-one and 5-hydroxy-2,3-dimethylisoindol-1-one

The compounds 5-(benzyloxy)-2-methylisoindole-1-one (11136-1-2) and 5-(benzyloxy)-2,3-dimethylisoindole-1- A mixture of ketones (11154-1-2) (675 mg) was dissolved in methanol (8 mL), Pd/C (200 mg, 0.3 g/g) was added, hydrogen was passed through for reaction at room temperature for 1 h, and the reaction solution was suction filtered , the filtrate was concentrated and separated by high performance liquid chromatography to obtain 153 mg of 5-hydroxy-2-methylisoindol-1-one (11136-1) as a white solid and 5-hydroxy-2,3-dimethylisoindole -1-One (11154-1) White solid 72 mg.

Compound 5-hydroxy-2-methylisoindol-1-one: ¹ H NMR (400 MHz, d ₆ -DMSO) δ (ppm): 10.07 (br.s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J = 8.2 Hz, 1H), 4.33 (s, 2H), 3.01 (s, 3H).

MS (ESI, pos.ion) m/z: 164.10 [M+H] ⁺ .

Compound 5-hydroxy-2,3-dimethylisoindol-1-one: ¹ H NMR (400 MHz, d ₆ -DMSO) δ (ppm): 10.09 (br.s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 6.91 (s, 1H), 6.84 (d, J = 8.2 Hz, 1H), 4.42 (q, J = 6.6 Hz, 1H), 2.95 (s, 3H), 1.37 (d, J = 6.7 Hz, 3H).

MS (ESI, pos.ion) m/z: 178.10 [M+H] ⁺ .

Step 4: Compound ( 2R )-(2-methyl-1-oxoisoindol-5-yl)1-acetyl-4-(3-(cyclopropylmethoxy)-4-( Synthesis of difluoromethoxy)phenyl)pyrrolidine-2-carboxylate (Example 140)

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120 mg, 0.32 mmol) and 5-hydroxy-2-methylisoindol-1-one (58 mg, 0.36 mmol) in dichloromethane (4 mL) and N , N -dimethylformamide (2 mL) , was added N -hydroxy-7-azabenzotriazole (89 mg, 0.65 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (187 mg) , 0.98 mmol) and N , N -diisopropylethylamine (169 mg, 1.31 mmol), reacted at room temperature for 11 h, concentrated under reduced pressure to remove the solvent, added water (20 mL), extracted with ethyl acetate (10 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 35/1) to obtain 132 mg of white solid, Yield 79%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.83 (d, J = 6.9 Hz, 1H), 7.29 (s, 1H), 7.09 – 7.22 (m, 2H), 6.78 – 6.90 (m, 2H) ), 6.61 (t, J _FH = 75.6 Hz, 1H), 4.61 – 4.72 (m, 1H), 4.35 (s, 2H), 3.95 – 4.05 (m, 1H), 3.87 (d, J = 5.7 Hz, 2H ), 3.62 – 3.75 (m, 1H), 3.46 – 3.59 (m, 1H), 3.18 (s, 3H), 2.74 – 2.87 (m, 1H), 2.16 – 2.28 (m, 1H), 2.15 (s, 3H) ), 1.21 – 1.32 (m, 1H), 0.56 – 0.69 (m, 2H), 0.27 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 515.25 [M+H] ⁺ .

Step 5: Compound ( 2R )-(2,3-Dimethyl-1-oxoisoindol-5-yl)1-acetyl-4-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate (Example 141)

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120 mg, 0.32 mmol) and 5-hydroxy-2,3-dimethylisoindol-1-one (63 mg, 0.36 mmol) in dichloromethane (4 mL) and N , N -dimethylformamide ( 2 mL), add N -hydroxy-7-azabenzotriazole (89 mg, 0.65 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (187 mg, 0.98 mmol) and N , N -diisopropylethylamine (169 mg, 1.31 mmol), reacted at room temperature for 11 h, concentrated under reduced pressure to remove the solvent, added water (20 mL), extracted with ethyl acetate ( 10 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 35/1) to obtain a white solid 137 mg, yield 80%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.82 (d, J = 7.7 Hz, 1H), 7.26 (s, 1H), 7.16 – 7.21 (m, 1H), 7.15 (d, J = 9.0 Hz, 1H), 6.80 – 6.90 (m, 2H), 6.62 (t, J _FH = 75.6 Hz, 1H), 4.66 – 4.69 (m, 1H), 4.37 – 4.47 (m, 1H), 3.96 – 4.05 (m , 1H), 3.87 (d, J = 6.4 Hz, 2H), 3.65 – 3.75 (m, 1H), 3.48 – 3.59 (m, 1H), 3.11 (s, 3H), 2.77 – 2.88 (m, 1H), 2.16 – 2.28 (m, 1H), 2.16 (s, 3H), 1.47 (d, J = 5.9 Hz, 3H), 1.21 – 1.32 (m, 1H), 0.60 – 0.69 (m, 2H), 0.30 – 0.41 ( m, 2H).

MS (ESI, pos.ion) m/z: 529.30 [M+H] ⁺ .

Example 142: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((6-fluoro Pyridin-2-yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (203 mg, 0.55 mmol), (6-fluoropyridin-2-yl)methanamine dihydrochloride (162 mg, 0.81 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt (521 mg, 2.72 mmol) and N -hydroxy-7-azabenzotriazole (149 mg, 1.09 mmol) were dissolved in dichloromethane (5 mL) and added dropwise to this solution at 0°C N , N -diisopropylethylamine (0.7 mL, 4.0 mmol), reacted at room temperature for 16 h, washed with water (15 mL), extracted with dichloromethane (5 mL × 3), and the organic phase was dried over anhydrous sodium sulfate , the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain 163 mg of a pale yellow solid with a yield of 62%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.75 – 7.81 (m, 1H), 7.24 (d, J = 5.4 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.90 ( s, 1H), 6.81 – 6.87 (m, 2H), 6.62 (t, J _FH = 75.6 Hz, 1H), 4.54 – 4.63 (m, 3H), 3.94 – 3.98 (m, 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.57 (t, J = 10.7 Hz, 1H), 3.30 – 3.42 (m, 1H), 2.54 – 2.62 (m, 1H), 2.42 – 2.51 (m, 1H), 2.16 (s, 3H), 1.24 – 1.33 (m, 1H), 0.64 – 0.69 (m, 2H), 0.35 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 478.30 [M+H] ⁺ .

Example 143: Compound (6-(ethyl(methyl)carbamoyl)pyridin-2-yl)methyl( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy) yl)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 6-(ethyl(methyl)carbamoyl)methyl picolinate

Compound 2,6-pyridinedicarboxylate monomethyl ester (500 mg, 2.76 mmol), N -ethylmethylamine (327 mg, 5.53 mmol), 1-ethyl-(3-dimethylaminopropyl) ) carbodiimide hydrochloride (2.65 g, 13.8 mmol) and N -hydroxy-7-azabenzotriazole (750 mg, 5.51 mmol) were dissolved in dichloromethane (10 mL) and cooled to 0 °C, add N , N -diisopropylethylamine (2.1 g, 16.0 mmol), react at room temperature for 5 h, add water (20 mL), extract with dichloromethane (15 mL × 3), the organic phase is washed with anhydrous It was dried over sodium sulfate, concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 2/1) to obtain 592 mg of light brown liquid with a yield of 96%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.16 – 8.19 (m, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.85 (t, J = 6.3 Hz, 1H), 4.02 ( s, 3H), 3.25 – 3.30 (m, 2H), 3.11 – 3.12 (m, 3H), 1.24 – 1.28 (m, 3H).

MS (ESI, pos.ion) m/z: 223.20 [M+H] ⁺ .

Step 2: Synthesis of compound N -ethyl-6-(hydroxymethyl) -N-picolinamide

The compound 6-(ethyl(methyl)carbamoyl)picolinate methyl ester (370 mg, 1.66 mmol) was dissolved in tetrahydrofuran (6 mL), and lithium borohydride (354 mg, 16.6 mmol) was added under ice bath. , the reaction was stopped after 1 h at room temperature, saturated aqueous sodium chloride solution (10 mL) was added, extracted with ethyl acetate (10 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography Separation (eluent: dichloromethane/methanol (v/v) = 30/1) gave 116 mg of pale yellow liquid, yield 36%.

¹ H NMR (400 MHz, d ₆ -DMSO) δ (ppm): 7.90 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 5.49 (t, J = 5.9 Hz, 1H), 4.56 – 4.58 (m, 2H), 3.47 (q, J = 0.8 Hz, 1H), 3.22 (q, J = 1.2 Hz, 1H), 2.96 ( s, 1.7H), 2.88 (s, 1.3H), 1.14 (t, J = 7.1 Hz, 1.2H), 1.08 (t, J = 7.0 Hz, 1.8H).

MS (ESI, pos.ion) m/z: 195.20 [M+H] ⁺ .

Step 3: Compound (6-(ethyl(methyl)carbamoyl)pyridin-2-yl)methyl( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy) )-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (70 mg, 0.19 mmol), N -ethyl-6-(hydroxymethyl) -N -picoline amide (52 mg, 0.27 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Imine hydrochloride (181 mg, 0.94 mmol) and N -hydroxy-7-azabenzotriazole (51 mg, 0.37 mmol) were dissolved in dichloromethane (5 mL), cooled to 0 °C, added N , N -diisopropylethylamine (146 mg, 0.13 mmol), reacted at room temperature for 12 h, added water (15 mL), extracted with dichloromethane (5 mL × 3), the organic phase was dried over anhydrous sodium sulfate, The solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 25/1) to obtain 216 mg of a light yellow viscous solid with a yield of 49%.

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.84 (t, J = 7.7 Hz, 1H), 7.51 – 7.55 (m, 2H), 7.15 (d, J = 8.6 Hz, 1H), 6.84 ( s, 1H), 6.80 – 6.84 (m, 1H), 6.63 (t, J _FH = 71.5 Hz, 1H), 5.26 – 5.47 (m, 2H), 4.59 – 4.64 (m, 1H), 3.96 – 4.01 (m , 1H), 3.88 (d, J = 6.9 Hz, 2H), 3.56 – 3.68 (m, 2H), 3.41 – 3.52 (m, 1H), 3.33 – 3.40 (m, 1H), 3.09 (s, 1.8H) , 3.01 (s, 1.2H), 2.70 – 2.77 (m, 1H), 2.15 (s, 3H), 2.06 – 1.15 (m, 1H), 1.25 – 1.34 (m, 1H), 1.17 – 1.26 (m, 3H) ), 0.65 – 0.69 (m, 2H), 0.35 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 546.30 [M+H] ⁺ .

Example 144: Compound ( 2R )-1-isoindolinone-5-yl 1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzene yl)pyrrolidine-2-carboxylate

The compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (128 mg, 0.35 mmol), 5-hydroxyisoindol-1-one (61 mg, 0.41 mmol) and N -hydroxy-7-azabenzotriazole (91 mg, 0.67 mmol) in N , N -dimethyl carbodiimide (15 mL), cooled to 0°C, added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (186 mg, 0.97 mmol) and N , N -Diisopropylethylamine (127 mg, 1.29 mmol), reacted at room temperature for 7 h, concentrated under reduced pressure to remove the solvent, added water (20 mL), extracted with ethyl acetate (10 mL × 2), the organic phase was washed with anhydrous sulfuric acid It was dried over sodium, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 35/1) to obtain 59 mg of a light brown solid with a yield of 34%.

¹ H NMR (400 MHz, CD ₃ OD) δ (ppm): 7.83 (d, J = 8.3 Hz, 1H), 7.33 (s, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.15 (d , J = 8.2 Hz, 1H), 7.07 (s, 1H), 6.96 – 6.99 (m, 1H), 6.76 (t, J _FH = 74.9 Hz, 1H), 4.50 (s, 2H), 4.14 – 4.18 (m , 1H), 3.90 (d, J = 7.0 Hz, 2H), 3.62 – 3.77 (m, 3H), 2.85 – 2.93 (m, 1H), 2.19 – 2.28 (m, 1H), 2.20 (s, 3H), 1.21 – 1.28 (m, 1H), 0.59 – 0.63 (m, 2H), 0.30 – 0.34 (m, 2H).

MS-ESI: m/z 501.05 [M+H] ⁺ .

Example 145: 1-Hydroxy-1,3-dihydrobenzo[ c ][1,2]oxaborol-5-yl( 2R )-1-acetoxy-4-(6- Ethoxypyridin-3-yl)pyrrolidine-2-carboxylate

Step 1: Synthesis of compound 2-ethoxy-5-iodopyridine

2-Hydroxy-5-iodopyridine (1.50 g, 4.00 mmol), anhydrous potassium carbonate (1.90 g, 14.0 mmol), DMF (12 ml) were added to the sealed tube, and after stirring at room temperature for 30 min, ethyl iodide was added. alkane (3 g, 19.2 mmol), and the reaction was stirred at 80 °C for 12 h. Ethyl acetate (100 mL) was added to dilute, the organic phase (40 mL) was washed with saturated ammonium chloride solution, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the concentrate was separated by silica gel column chromatography (eluent). : petroleum ether/ethyl acetate (v/v) = 4/1) to give a yellow solid (1.00 g, 59% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.50 (d, J = 2.3 Hz, 1H), 7.41 (dd, J = 9.5, 2.5 Hz, 1H), 6.39 (d, J = 9.5 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).

MS (ESI, pos.ion) m/z: 250.00 [M+H] ⁺ .

Step 2: compound 1-tert-butyl 2-methyl (R) -4- (6- ethoxy-pyridin-3-yl) -1 H - pyrrole -1,2- (2 H, 5 H) - two Synthesis of Formate

( R )-1-tert-butyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)- 1H -pyrrole-1,2( 2H , 5H )-dicarboxylate (2.00 g, 4.40 mmol), 2-ethoxy-5-iodopyridine (1.00 g, 4.00 mmol), potassium phosphate (3.40 g, 16.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl ₂ ) (147 mg, 0.20 mmol) were mixed in dry 1,4 - Dioxane (10 mL) solution, reacted at 100 °C for 22 h under nitrogen protection, cooled to room temperature, filtered with suction, added water (50 mL) to the filtrate, extracted with ethyl acetate (15 mL × 3), The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the concentrated solution was separated by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/4) to obtain a yellow liquid (0.80 g, 57% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.46 (dd, J = 9.5, 2.6 Hz, 1H), 7.14 – 7.20 (m, 1H), 6.58 (d, J = 9.5 Hz, 1H), 5.79 – 5.88 (m, 1H), 5.04 – 5.16 (m, 1H), 4.35 – 4.56 (m, 2H), 3.94 – 4.03 (m, 2H), 3.75 (d, J = 3.9 Hz, 3H), 1.52 ( s, 3H), 1.45 (s, 6H), 1.32 – 1.39 (m, 3H).

MS (ESI, pos.ion) m/z: 349.65 [M+H] ⁺ .

Step 3: Synthesis of compound 1-(tert-butyl)2-methyl( 2R )-4-(6-ethoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate

The compound 1-tert-butyl 2-methyl (R) -4- (6- ethoxy-pyridin-3-yl) -1 H - pyrrole -1,2- (2 H, 5 H) - dicarboxylic acid The ester (0.8 g, 2.3 mmol) was dissolved in methanol (15 mL), Pd/C (80 mg, 0.10 g/g) was added, hydrogen was passed through, the reaction was carried out at room temperature for 23 h, the catalyst was removed by filtration, and the filtrate was concentrated to obtain a yellow oil compound (639 mg, 79% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.19 – 7.26 (m, 1H), 7.08 – 7.12 (m, 1H), 6.56 (d, J = 9.4 Hz, 1H), 4.27 – 4.40 (m , 1H), 3.91 – 3.99 (m, 0.5H), 3.95 (q, J = 7.2 Hz, 2H), 3.82 – 3.89 (m, 0.5H), 3.75 (d, J = 6.3 Hz, 3H), 3.27 – 3.38 (m, 1H), 3.05 – 3.17 (m, 1H), 2.51 – 2.63 (m, 1H), 1.84 – 1.98 (m, 1H), 1.38 – 1.49 (m, 9H), 1.34 (t, J = 7.2 Hz, 3H).

MS (ESI, pos.ion) m/z: 351.20 [M+H] ⁺ .

Step 4: Synthesis of Compound (2R )-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

Compound 1-(tert-butyl)2-methyl( 2R )-4-(6-ethoxypyridin-3-yl)pyrrolidine-1,2-dicarboxylate (0.64 g, 1.80 mmol) It was dissolved in dichloromethane (6 mL) solution, 4 mol/L HCl in ethyl acetate solution (8 mL) was added, stirred at room temperature for 50 min, concentrated under reduced pressure to remove the solvent to obtain a pale yellow solid (585 mg, yield 100%).

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.83 – 7.89 (m, 1H), 7.70 – 7.76 (m, 1H), 6.74 (d, J = 9.2 Hz, 1H), 4.61 (dd, J = 10.5, 7.5 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.72 – 3.80 (m, 1H), 3.53 – 3.67 (m, 1H), 3.27 – 3.34 (m, 1H), 2.75 – 2.86 (m, 1H), 2.20 (q, J = 12.0 Hz, 1H), 1.37 (t, J = 7.2 Hz, 3H).

MS (ESI, pos.ion) m/z: 251.20 [M+H-HCl] ⁺ .

Step 5: Synthesis of Compound (2R )-1-Acetyl-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid methyl ester

Compound ( 2R )-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (520 mg, 1.80 mmol) was dissolved in dichloromethane (8 mL), N , N -diisopropylethylamine (1.89 mL, 10.9 mmol) was added, cooled to 0 °C, acetyl chloride (0.39 mL, 5.4 mmol) was added, the reaction was stopped after stirring at room temperature for 3 h, and water (15 mL) was added. , extracted with dichloromethane (10 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to give a brown liquid (378 mg, 71%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.28 (d, J = 2.6 Hz, 1H), 7.12 – 7.17 (m, 1H), 6.58 (d, J = 9.3 Hz, 1H), 4.42 – 4.51 (m, 1H), 3.91 – 4.02 (m, 2H), 3.83 – 3.91 (m, 1H), 3.73 – 3.79 (m, 3H), 3.52 (t, J = 10.4 Hz, 1H), 3.15 – 3.27 ( m, 1H), 2.53 – 2.63 (m, 1H), 2.11 (s, 3H), 1.89 – 1.97 (m, 1H), 1.33 – 1.38 (m, 3H).

MS (ESI, pos.ion) m/z: 293.15 [M+H] ⁺ .

Step 6: Synthesis of (2R )-1-Acetyl-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid

Compound ( 2R )-methyl 1-acetyl-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylate (350 mg, 1.20 mmol) was dissolved in tetrahydrofuran (6 mL) In a mixed solvent of water (3 mL), lithium hydroxide monohydrate (100 mg, 2.40 mmol) was added, and the reaction was stopped after 1.5 h at 50 °C. Diluted hydrochloric acid was added to adjust the pH of the solution to 1. Silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 8/1) gave a white solid (375 mg, 99%).

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.60 – 7.64 (m, 2H), 6.55 (d, J = 9.0 Hz, 1H), 4.32 (dd, J = 16.9, 8.0 Hz, 1H) , 4.10 – 4.16 (m, 0.6H), 4.03 (q, J = 7.1 Hz, 2H), 3.93 – 3.98 (m, 0.4H), 3.51 – 3.58 (m, 0.4H), 3.25 – 3.33 (m, 0.6 H), 3.09 – 3.24 (m, 1H), 2.57 – 2.79 (m, 1H), 2.10 (s, 1H), 2.01 (s, 2H), 1.83 – 1.98 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H).

MS (ESI, pos.ion) m/z: 279.25 [M+H] ⁺ .

Step 7: 1-Hydroxy-1,3-dihydrobenzo[ c ][1,2]oxaborolane-5-yl( 2R )-1-acetoxy-4-(6-ethyl) Synthesis of Oxypyridin-3-yl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid (200 mg, 0.64 mmol), 2-hydroxymethyl-5-hydroxy Phenylboronic acid half ester (114 mg, 0.76 mmol) was dissolved in N , N -dimethylformamide (10 mL), and N -hydroxy-7-azabenzotriazole (265 mg, 1.91 mmol) was added , 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (365 mg, 1.91 mmol) and N , N -diisopropylethylamine (494 mg) were added in an ice bath , 3.81 mmol), reacted at room temperature for 23 h, added water (20 mL), stirred for 5 min, extracted with dichloromethane (5 mL × 2), dried the organic phase with anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography Isolation (eluent: dichloromethane/methanol (v/v) = 15/1) gave a white solid (100 mg, 56% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.75 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 9.4, 2.5 Hz, 1H), 7.18 – 7.23 (m, 1H), 7.11 (s, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 9.4 Hz, 1H), 5.03 (s, 2H), 4.63 – 4.72 (m, 1H), 3.90 – 4.03 (m, 3H), 3.60 (t, J = 10.4 Hz, 1H), 3.25 – 3.39 (m, 1H), 2.68 – 2.82 (m, 1H), 2.16 (s, 3H), 2.09 – 2.13 (m, 1H) ), 1.33 (t, J = 7.2 Hz, 3H).

MS (ESI, pos.ion) m/z: m/z: 411.10 [M+H] ⁺ .

Example 146: (6-(Ethyl(methyl)carbamoyl)pyridin-2-yl)methyl( 2R )-1-acetyl-4-(6-ethoxypyridine-3- yl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(6-ethoxypyridin-3-yl)pyrrolidine-2-carboxylic acid (100 mg, 0.36 mmol, Example 145 step 6), N -ethyl yl-6-(hydroxymethyl) -N -picolinamide (74 mg, 0.38 mmol) was dissolved in N , N -dimethylformamide (5 mL) and N -hydroxy-7-nitrogen was added Heterobenzotriazole (132 mg, 0.95 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.95 mmol) and N , N -diisopropylethylamine (247 mg, 1.90 mmol), reacted at room temperature for 23 h, concentrated under reduced pressure to remove the solvent, added water (10 mL), stirred for 5 min, extracted with dichloromethane (20 mL × 2), The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain a white solid (60 mg, product rate: 42%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.77 – 7.85 (m, 1H), 7.45 – 7.54 (m, 2H), 7.23 – 7.26 (m, 1H), 7.15 – 7.18 (m, 1H) , 6.58 (d, J = 9.4 Hz, 1H), 5.36 – 5.44 (m, 1H), 5.21 – 5.31 (m, 1H), 4.52 – 4.62 (m, 1H), 3.93 – 4.04 (m, 2H), 3.83 – 3.92 (m, 1H), 3.48 – 3.62 (m, 2H), 3.29 – 3.37 (m, 1H), 3.19 – 3.28 (m, 1H), 3.07 (s, 2H), 2.98 (s, 1H), 2.56 – 2.69 (m, 1H), 2.11 (s, 3H), 2.00 – 2.05 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.20 – 1.23 (m, 1H), 1.12 – 1.19 (m , 2H).

MS (ESI, pos.ion) m/z: 455.20[M+H] ⁺ .

Example 147: ( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (1-oxoiso Indolin-5-yl)pyrrolidine-2-carboxamide

Compound ( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (151 mg, 0.41 mmol, Example 18 step 1), 5-aminoisoindolin-1-one (89 mg, 0.60 mmol) and N -hydroxy-7-azabenzotriazole (110 mg, 0.81 mmol) were dissolved in Dichloromethane/anhydrous N , N -dimethylformamide (8 mL, (v/v) = 3/1), add 1-ethyl-3-(3-dimethylaminopropane) in an ice bath base) carbodiimide hydrochloride (243 mg, 1.26 mmol) and N , N -diisopropylethylamine (268 uL, 1.62 mmol), and stirred at room temperature for 3 h. Saturated brine (20 mL) was added, the aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent). : dichloromethane/methanol (v/v) = 50/1) to give an off-white solid (161 mg, 79%, HPLC 98.44%).

¹ H NMR (600 MHz, CDCl ₃ ): δ (ppm) 10.25 (s, 1H), 8.93 (s, 1H), 8.11 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.11 ( d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.60 (t, J = 75.6 Hz, 1H), 4.76 (t, J = 7.4 Hz, 1H), 4.30 – 4.16 (m, 2H), 4.07 – 3.96 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.72 (t, J = 9.9 Hz, 1H), 3.48 – 3.36 (m, 1H), 2.73 – 2.61 (m, 1H), 2.37 – 2.27 (m, 1H), 2.24 (s, 3H), 1.30 – 1.21 (m, 1H), 0.67 – 0.60 (m, 2H), 0.38 – 0.30 (m, 2H).

MS (ESI, pos.ion) m/z: 500.20 [M+H] ⁺ .

Example 148: (6-(Methyl( p -tolyl)carbamoyl)pyridin-2-yl)methyl( 2S )-1-acetyl-4-(3-(cyclopropylmethyl) oxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

The compound ( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (107 mg, 0.29 mmol, Example 18 step 1), 6-hydroxymethyl- N -methyl- N -p-tolyl-picolinamide (90 mg, 0.35 mmol) and N -hydroxy-7-azabenzotri Azole (74 mg, 0.54 mmol) was dissolved in dichloromethane (10 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (157 mg, 81 mmol) and N , N -diisopropylethylamine (179 uL, 1.08 mmol), and stirred at room temperature for 3 h. Saturated brine (20 mL) was added, the aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent). : dichloromethane/methanol (v/v) = 50/1) to give a white solid (80 mg, 79% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.57 (s, 1H), 7.38 – 7.18 (m, 2H), 7.11 (d, J = 8.1 Hz, 1H), 7.03 – 6.86 (m, 4H) ), 6.84 – 6.76 (m, 2H), 6.60 (t, J = 75.5 Hz, 1H), 5.25 – 4.98 (m, 2H), 4.59 – 1.49 (m, 1H), 3.94 (t, J = 8.0 Hz, 1H), 3.85 (d, J = 6.8 Hz, 2H), 3.61 (t, J = 10.1 Hz, 1H), 3.51 – 3.34 (m, 4H), 2.74 – 2.64 (m, 1H), 2.25 (s, 3H) ), 2.11 (s, 3H), 2.16 – 2.02 (m, 1H), 1.33 – 1.21 (m, 1H), 0.69 – 0.58 (m, 2H), 0.41 – 0.28 (m, 2H).

MS (ESI, pos.ion) m/z: 608.20 [M+H] ⁺ .

Example 149: ( 2S )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((3-oxo Isoindolin-5-yl)methyl)pyrrolidine-2-carboxamide

The compound ( 2S )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (86 mg, 0.23 mmol), 6-aminomethylisoindolin-1-one (53 mg, 0.33 mmol) and N -hydroxy-7-azabenzotriazole (73 mg, 0.54 mmol) in dichloro Methane/anhydrous N , N -dimethylformamide (8 mL, (v/v) = 1/1), add 1-ethyl-3-(3-dimethylaminopropyl) in an ice bath Carbodiimide hydrochloride (157 mg, 81 mmol) and N , N -diisopropylethylamine (179 uL, 1.08 mmol) were stirred at room temperature for 3 h. Saturated brine (20 mL) was added, the aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent). : dichloromethane/methanol (v/v) = 20/1) to give a white solid (66 mg, 55% yield).

¹ H NMR (600 MHz, CDCl ₃ ): δ (ppm) 8.51 (d, J = 7.2 Hz, 1H), 7.98 (s, 1H), 7.50 – 7.47 (m, 2H), 7.27 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 1.7 Hz, 1H), 6.85 (dd, J = 8.2, 1.8 Hz, 1H), 6.61 (t, J = 75.6 Hz, 1H), 5.05 – 4.98 (m, 1H), 4.68 (t, J = 8.4 Hz, 1H), 4.13 (d, J = 17.3 Hz, 1H), 3.99 – 3.93 (m, 1H), 3.92 (d , J = 7.7 Hz, 1H), 3.87 (d, J = 6.9 Hz, 2H), 3.86 – 3.83 (m, 1H), 3.70 (t, J = 10.7 Hz, 1H), 3.39 – 3.31 (m, 1H) , 2.67 – 2.62 (m, 1H), 2.37 – 2.30 (m, 1H), 2.15 (s, 3H), 1.30 – 1.24 (m, 1H), 0.66 – 0.62 (m, 2H), 0.37 – 0.33 (m, 2H).

MS (ESI, pos.ion) m/z: 514.20 [M+H] ⁺ .

Example 150: (2 R, 4 R ) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) - N - (1- oxoisoindolin-5-yl)pyrrolidine-2-carboxamide

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

Compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (5.0 g, 14.7 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) solution, cooled under nitrogen protection to -78°C, add 1.3 mol/L isopropylmagnesium chloride-lithium chloride solution in tetrahydrofuran (16 mL, 20.8 mmol), react for 1.5 h, slowly add N - Boc- 4-oxo- D -proline methyl ester (3.5 g, 14.0 mmol) in anhydrous tetrahydrofuran (20 mL), the reaction was continued at -78 °C for 4 h and then stopped, and saturated aqueous ammonium chloride solution (70 mL) and water (30 mL) were added successively, and extracted with ethyl acetate (35 mL × 2), 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: PE/EtOAc (v/v) = 3/1) to obtain light brown Oil (2.9 g, 43% yield). 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) 6.84 – 7.23 (m, 1H), 7.19 – 7.22 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.02 – 7.07 (m , 1H), 5.56 (d, J = 8.7 Hz, 1H), 4.38 – 4.45 (m, 1H), 3.89 (d, J = 6.9 Hz, 2H), 3.64 – 3.66 (m, 3H), 3.55 – 3.60 ( m, 2H), 2.62 – 2.69 (m, 1H), 2.18 – 2.25 (m, 1H), 1.37 – 1.41 (m, 9H), 1.19 – 1.28 (m, 1H), 0.55 – 0.59 (m, 2H), 0.32 – 0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 384.15 [MH ₂ O- t -Bu+2H] ⁺ .

Step 2: Compound ( 2R , 4S )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4- Synthesis of Hydroxypyrrolidine-2-carboxylic Acid

Compound (2 R ,4 S )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrole Alkane-1,2-dicarboxylate (770 mg, 1.68 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (10 mL), lithium hydroxide monohydrate (285 mg, 6.79 mmol) was added, and the The warm reaction was stopped after 1.5 h, and hydrochloric acid was added to adjust the pH of the solution to 4, followed by extraction with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid (741 mg, yield 99 %).

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.23 (s, 1H), 7.06 – 7.14 (m, 2H), 6.76 (t, J _FH = 75.6 Hz, 1H), 4.45 – 4.53 (m , 1H), 3.94 (d, J = 6.6 Hz, 2H), 3.67 – 3.76 (m, 2H), 2.73 – 2.79 (m, 1H), 2.42 – 2.45 (m, 1H), 1.48 – 1.50 (m, 9H) ), 1.24 – 1.35 (m, 1H), 0.60 – 0.68 (m, 2H), 0.34 – 0.42 (m, 2H).

MS (ESI, pos.ion) m/z: 466.10 [M+Na] ⁺ .

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

( 2R , 4S )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine -2-carboxylic acid (817 mg, 1.84 mmol) was dissolved in dichloromethane (25 mL) solution, N , N -diisopropylethylamine (717 mg, 5.55 mmol) was added, cooled in an ice bath, methyl methane was added Sulfonyl chloride (317 mg, 2.77 mmol), react at room temperature for 3 h, add water (30 mL) to wash the organic phase, separate the organic phase, extract the aqueous phase with dichloromethane (5 mL × 2), combine the organic phases, use It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 6/1) to obtain a pale yellow liquid (681 mg, yield 87%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.24 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.96 (dd, J = 8.3, 2.0 Hz, 1H), 6.67 (t, J _FH = 75.2 Hz, 1H), 4.66 – 4.82 (m, 1H), 3.91 (d, J = 6.9 Hz, 2H), 3.62 – 3.75 (m, 2H), 2.43 – 2.46 ( m, 1H), 2.29 – 2.32 (m, 1H), 1.51 (s, 9H), 1.26 – 1.37 (m, 1H), 0.66 – 0.71 (m, 2H), 0.37 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 448.10 [M+Na] ⁺ .

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

The compound (1 S ,4 R )-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa- 5-Azabicyclo[2.2.1]heptane-5-carboxylate (1.4 g, 3.29 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (TFA) (824 mg, 7.23 mmol) was added, The reaction was carried out at room temperature for 2 h, water (40 mL) was added to wash the organic phase, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v ) = 1/2) to give a light brown solid (1.2 g, 86% yield).

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.16 – 7.20 (m, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.01 – 7.06 (m, 1H), 6.79 (t, J _FH = 75.4 Hz, 1H), 6.24 – 6.29 (m, 1H), 5.06 – 5.12 (m, 1H), 4.51 – 4.62 (m, 2H), 3.96 (d, J = 6.8 Hz, 2H), 1.49 – 1.54 (m, 9H), 1.24 – 1.37 (m, 1H), 0.62 – 0.67 (m, 2H), 0.38 – 0.42 (m, 2H).

MS (ESI, pos.ion) m/z: 370.10 [M- t- Bu+2H] ⁺ .

Step 5: Compound ( 2R , 4R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Synthesis of formic acid

Compound ( R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1 H -pyrrole-2-carboxylic acid (1.6 g, 3.80 mmol) was dissolved in ethanol (27 mL) and anhydrous tetrahydrofuran (3 mL), triphenylphosphine rhodium chloride (452 mg, 0.49 mmol) and triethylamine (572 mmol) were added. mg, 5.65 mmol), passed into hydrogen and reacted at room temperature under 0.5 MPa pressure for 3 days, then concentrated the reaction solution, added water (27 mL), added dilute hydrochloric acid to adjust pH=1, extracted with ethyl acetate (30 mL × 3) , the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to obtain a pale yellow liquid (1.2 g, yield rate of 75%, 4R: 4S = 4 : 1), resolution via chiral column to give (2 R, 4 R) -1- ( tert-butoxycarbonyl) -4- (3- (cyclopropylmethoxy) - 4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid. Synthetic reference: Carboxylate-Directed Highly Stereoselective Homogeneous Hydrogenation of Cyclic Olefins with Wilkinson's Catalyst. Organic Letters. 2003 Vol. 5, No. 9 1587 - 1589 .

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.10 (d, J = 8.2 Hz, 1H), 7.00 – 7.03 (m, 1H), 6.86 – 6.90 (m, 1H), 6.73 (t, J _FH = 75.7 Hz, 1H), 4.38 – 4.46 (m, 1H), 3.89 – 3.97 (m, 1H), 3.92 (d, J = 6.9 Hz, 2H), 3.49 – 3.57 (m, 1H), 3.35 – 3.41 (m, 1H), 2.43 – 2.51 (m, 1H), 2.32 – 2.39 (m, 1H), 1.46 – 1.49 (m, 9H), 1.26 – 1.35 (m, 1H), 0.61 – 0.66 (m, 2H) ), 0.36 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 372.10 [M- t- Bu+2H] ⁺ .

Step 6: Compound ( 2R , 4R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((1-oxo Synthesis of isoindolin-5-yl)carbamoyl)pyrrolidine-1-carboxylate

The compound ( 2R , 4R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (120 mg, 0.28 mmol), 5-aminoisoindol-1-one (50 mg, 0.34 mmol) and N -hydroxy-7-azabenzotriazole (76 mg, 0.56 mmol) in dichloro Methane (12 mL) and dry DMF (4 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (167 mg, 0.87 mmol) and N , N - Diisopropylethylamine (169 mg, 1.31 mmol) was reacted at room temperature for 10 h, concentrated under reduced pressure, the residue was added with water (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined and washed with anhydrous It was dried over sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 23/1) to obtain a white solid (83 mg, yield 53%).

Compound 11178-3: MS (ESI, pos.ion) m/z: 558.20 [M+H] ⁺ .

Step 7: Compound ( 2R , 4R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (1-oxoisoindoline Synthesis of -5-yl)pyrrolidine-2-carboxamide hydrochloride

Compound (2 R ,4 R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((1-oxoisoindium) Indolin-5-yl)carbamoyl)pyrrolidine-1-carboxylate (11178-3) (83 mg, 0.15 mmol) was dissolved in dichloromethane (4 mL) solution, and 4 mol/L HCl was added A solution of 1,4-dioxane (1.5 mL) was stirred at room temperature for 2 h, and the solvent was removed to give a white solid (74 mg, 100% yield).

Step 8: Compound (2 R, 4 R) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) - N - (1- Synthesis of oxoisoindolin-5-yl)pyrrolidine-2-carboxamide

Compound ( 2R , 4R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N- (1-oxoisoindoline-5 -yl)pyrrolidine-2-carboxamide hydrochloride (73 mg, 0.15 mmol) was dissolved in dichloromethane (8 mL), cooled in an ice bath, added with N , N -diisopropylethylamine ( 191 mg, 1.48 mmol) and acetyl chloride (59 mg, 0.75 mmol), the reaction was stopped after stirring at room temperature for 1 h, water (20 mL) was added and stirred for 2 min, the organic phase was separated, 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 residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 35/1) to obtain a brown solid (27 mg) , yield 36%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 10.18 (br.s, 1H), 8.08 (s, 1H), 7.46 – 7.58 (m, 1H), 7.14 (d, J = 7.4 Hz, 1H ), 7.01 – 7.10 (m, 1H), 6.86 – 6.91 (m, 2H), 6.62 (t, J _FH = 75.6 Hz, 1H), 4.72 – 4.89 (m, 1H), 4.20 – 4.35(m, 2H) , 3.96 – 4.10 (m, 1H), 3.88 (d, J = 5.5 Hz, 2H), 3.61 – 3.74 (m, 1H), 3.32 – 3.53 (m, 1H), 2.59 – 2.74 (m, 1H), 2.37 – 2.53 (m, 1H), 2.26 (s, 3H), 1.23 – 1.34 (m, 1H), 0.60 – 0.71 (m, 2H), 0.31 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 500.05 [M+H] ⁺ .

Example 151: (2 R, 4 S ) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) - N - (1- oxoisoindolin-5-yl)pyrrolidine-2-carboxamide

Step 1: Compound ( 2R , 4S )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 -Synthesis of formic acid

Compound ( R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1 H -pyrrole-2-carboxylic acid (500 mg, 1.18 mmol, Example 150, step 4) was dissolved in ethanol (27 mL), added with Pd/C (400 mg) and triethylamine (178 mg, 1.76 mmol), passed through Hydrogen was reacted at room temperature for 12 h, then the reaction solution was suction filtered, and the filtrate was concentrated to obtain a light brown liquid (483 mg, yield 96%). Synthetic reference: Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2. J. Med. Chem. 2014, 57, 9042 - 9064 .

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.07 – 7.09 (m, 2H), 6.89 – 6.92 (m, 1H), 6.73 (t, J _FH = 75.8 Hz, 1H), 4.19 – 4.25 (m, 1H), 3.89 – 3.97 (m, 1H), 3.98 (d, J = 6.9 Hz, 2H), 3.44 (d, J = 10.6 Hz, 1H), 3.32 – 3.38 (m, 1H), 2.61 – 2.68 (m, 1H), 1.98 – 2.07 (m, 1H), 1.48 (s, 9H), 1.28 – 1.34 (m, 1H), 0.61 – 0.66 (m, 2H), 0.37 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 372.10 [M- t- Bu+2H] ⁺ .

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

Compound ( 2R , 4S )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (280 mg, 0.66 mmol), methanol (106 mg, 3.31 mmol) and N -hydroxy-7-azabenzotriazole (178 mg, 1.31 mmol) were dissolved in dichloromethane (8 mL) and 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (503 mg, 2.62 mmol) and N , N -diisopropylethylamine (339 mg, 2.62 mmol), room temperature After 8 h of reaction, water (20 mL) was added to stop the reaction, extracted with dichloromethane (5 mL × 2), 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). :PE/EtOAc (v/v) = 5/1) to give a colorless liquid (165 mg, 57% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.10 (d, J = 7.9 Hz, 1H), 6.77 – 6.81 (m, 2H), 6.59 (t, J _FH = 75.6 Hz, 1H), 4.30 – 4.40 (m, 1H), 4.02 – 4.06 (m, 0.6H), 3.91 – 3.95 (m, 0.4H), 3.84 – 3.86 (m, 2H), 3.76 (d, J = 7.1 Hz, 3H), 3.38 – 3.44 (m, 1H), 3.26 – 3.36 (m, 1H), 2.61 – 2.68 (m, 1H), 1.96 – 2.07 (m, 1H), 1.43 – 1.46 (m, 9H), 1.25 – 1.33 (m, 1H) , 0.62 – 0.67 (m, 2H), 0.33 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 386.40 [M- t- Bu+2H] ⁺ .

Step 3: Compound ( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride synthesis

The compound ( 2R , 4S )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1, 2-Dicarboxylate (11179-3) (4.03 g, 9.13 mmol) was dissolved in dichloromethane (50 mL) solution, and 3 mol/L HCl in 1,4-dioxane solution (20 mL) was added was stirred at room temperature for 4.5 h, and the solvent was removed to give a pale yellow solid (3.5 g, 100%).

¹ H NMR (400 MHz, CD ₃ OD) δ: (ppm) 7.14 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 8.3, 1.8 Hz , 1H), 6.76 (t, J _FH = 75.5 Hz, 1H), 4.61 – 4.65 (m, 1H), 3.94 (d, J = 6.9 Hz, 2H), 3.90 (s, 3H), 3.79 – 3.83 (m , 1H), 3.64 – 3.74 (m, 1H), 3.37 (t, J = 11.1 Hz, 1H), 2.82 – 2.89 (m, 1H), 2.20 – 2.29 (m, 1H), 1.27 – 1.35 (m, 1H) ), 0.63 – 0.68 (m, 2H), 0.37 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 342.15 [M+H-HCl] ⁺ .

Step 4: Compound (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2-carboxylic acid Synthesis of methyl esters

Compound ( 2R , 4S )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (3.5 g , 9.30 mmol) was dissolved in dichloromethane (50 mL), cooled in an ice bath, N , N -diisopropylethylamine (6.0 g, 46.0 mmol) and acetyl chloride (2.2 g, 28.0 mmol) were added , the reaction was stopped after stirring at room temperature for 2.5 h, water (50 mL) was added and stirred for 2 min, the organic phase was separated, the aqueous phase was extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure , and the residue was subjected to silica gel column chromatography (eluent: PE/EtOAc (v/v) = 1/3) to obtain a brown liquid (3.4 g, 96%).

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.09 – 7.13 (m, 1H), 6.82 (s, 1H), 6.78 – 6.81 (m, 1H), 6.60 (t, J _FH = 75.5 Hz , 1H), 4.45 – 4.49 (m, 1H), 3.91 – 3.95 (m, 1H), 3.84 – 3.87 (m, 2H), 3.77 (s, 3H), 3.60 (t, J = 10.4 Hz, 1H), 3.36 – 3.45 (m, 1H), 2.62 – 2.68 (m, 1H), 2.11 (s, 2.5H), 2.02 – 2.06 (m, 1H), 1.98 (s, 0.5H), 1.24 – 1.33 (m, 1H) ), 0.63 – 0.68 (m, 2H), 0.34 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 384.10 [M+H] ⁺ .

Step 5: Compound (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2-carboxylic acid Synthesis

Compound (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2-carboxylic acid Ester (11179-5) (3.4 g, 8.90 mmol) was dissolved in a mixed solvent of tetrahydrofuran (40 mL) and water (20 mL), then lithium hydroxide monohydrate (1.1 mg, 26.0 mmol) was added, and the reaction was carried out at 50 °C for 1 After h, it was stopped, cooled in an ice bath, diluted hydrochloric acid was added to adjust the pH of the solution to 1, tetrahydrofuran was removed under reduced pressure, extracted with ethyl acetate (25 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Obtained as a pale yellow solid (3.3 g, 100%).

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.09 – 7.12 (m, 1H), 7.01 – 7.05 (m, 1H), 6.87 – 6.93 (m, 1H), 6.54 – 6.90 (m, 1H) ), 4.64 – 4.68 (m, 0.2H), 4.43 – 4.47 (m, 0.8H), 4.22 – 4.26 (m, 0.2H), 4.08 – 4.12 (m, 0.8H), 3.91 – 3.94 (m, 2H) , 3.57 – 3.63 (m, 1H), 3.47 – 3.55 (m, 1H), 2.88 – 2.95 (m, 0.2H), 2.71 – 2.78 (m, 0.8H), 2.14 (s, 2.5H), 2.00 – 2.08 (m, 1H), 2.02 (s, 0.5H), 1.26 – 1.33 (m, 1H), 0.62 – 0.67 (m, 2H), 0.37 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 370.20 [M+H] ⁺ .

Step 6: Compound (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) - N - (1- Synthesis of oxoisoindolin-5-yl)pyrrolidine-2-carboxamide

Compound (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2-carboxylic acid (120 mg, 0.32 mmol), 5-aminoisoindol-1-one (57 mg, 0.38 mmol) and N -hydroxy-7-azabenzotriazole (88 mg, 0.65 mmol) in DCM (12 mL) ) and DMF (4 mL), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (187 mg, 0.98 mmol) and N , N -diisopropylethyl acetate Amine (169 mg, 1.31 mmol), reacted at room temperature for 8 h, concentrated under reduced pressure to remove the solvent, added water (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure , the residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 17/1) to obtain a pale yellow solid (122 mg, yield 75%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 10.20 (br.s, 1H), 8.35 (br.s, 1H), 8.08 (s, 1H), 7.44 – 7.58 (m, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.97 – 7.06 (m, 1H), 6.90 (s, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.61 (t, J _FH = 75.6 Hz, 1H ), 4.70 – 4.87 (m, 1H), 4.18 – 4.35(m, 2H), 3.96 – 4.09 (m, 1H), 3.87 (d, J = 6.6 Hz, 2H), 3.63 – 3.76 (m, 1H), 3.36 – 3.53 (m, 1H), 2.59 – 2.76 (m, 1H), 2.32 – 2.47 (m, 1H), 2.24 (s, 3H), 1.23 – 1.34 (m, 1H), 0.57 – 0.71 (m, 2H) ), 0.28 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 498.50 [MH] ^- .

Example 152: ( 2R , 4S )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropyl) methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Compound ( 2R , 4S )-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3- Synthesis of (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

Compound ( 2R , 4S )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (298 mg, 0.70 mmol, carried out step 1 of 151), 6-(hydroxymethyl) -N -methyl- N- (p-methylphenyl)pyridinamide (179 mg, 0.70 mmol) and 1-hydroxybenzene Natriazole (142 mg, 1.05 mmol) was dissolved in dry DMF (5 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (201 mg, 1.05 mmol) and N -methylmorpholine (142 mg, 1.40 mmol), reacted at room temperature for 17 h, added water (30 mL) to stop the reaction, extracted with ethyl acetate (15 mL × 2), combined the organic phases, washed with anhydrous sulfuric acid It was dried over sodium, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: PE/EtOAc (v/v) = 1/1) to obtain a white viscous solid (285 mg, yield 61%).

¹ H NMR (400 MHz, CDCl ₃ ): δ ppm 7.49 – 7.62 (m, 1H), 7.22 – 7.33 (m, 1H), 7.13 – 7.19 (m, 1H), 7.09 (d, J = 7.9 Hz, 1H ), 6.86 – 7.03 (m, 4H), 6.78 – 6.83 (m, 2H), 6.59 (t, J _FH = 75.6 Hz, 1H), 5.19 – 4.97 (m, 2H), 4.37 – 4.48 (m, 1H) , 4.05 – 4.09 (m, 0.5H), 3.92 – 3.96 (m, 0.5H), 3.82 – 3.86 (m, 2H), 3.46 (s, 3H), 3.26 – 3.44 (m, 2H), 2.62 – 2.74 ( m, 1H), 2.25 (s, 3H), 1.97 – 2.10 (m, 1H), 1.37 (s, 4.5H), 1.45 (s, 4.5H), 1.24 – 1.31 (m, 1H), 0.60 – 0.68 ( m, 2H), 0.31 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 666.30 [M+H] ⁺ .

Step 2: Compound ( 2R , 4S )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride

The compound ( 2R , 4S )-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3-(cyclo) Propylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (1184-6) (280 mg, 0.42 mmol) was dissolved in dichloromethane (12 mL) ) solution, added 4 mol/L HCl in 1,4-dioxane solution (5 mL), stirred at room temperature for 3 h, concentrated under reduced pressure to remove the solvent to obtain a pale yellow solid (297 mg, 100%, containing solvent ).

¹ H NMR (400 MHz, CD ₃ OD) δ: (ppm) 7.76 – 7.85 (m, 1H), 7.46 – 7.52 (m, 1H), 7.29 – 7.36 (m, 1H), 7.09 – 7.16 (m, 2H) ), 7.00 – 7.08 (m, 4H), 6.94 – 6.97 (m, 1H), 6.75 (t, J _FH = 75.6 Hz, 1H), 5.29 – 5.39 (m, 2H), 4.73 – 4.78 (m, 1H) , 3.95 (d, J = 6.8 Hz, 2H), 3.82 – 3.87 (m, 1H), 3.71 – 3.78 (m, 1H), 3.36 – 3.47 (m, 1H), 3.45 (s, 3H), 2.87 – 2.95 (m, 1H), 2.30 – 2.43 (m, 1H), 2.24 (s, 3H), 1.26 – 1.38 (m, 1H), 0.61 – 0.68 (m, 2H), 0.35 – 0.42 (m, 2H).

MS (ESI, pos.ion) m/z: 566.20 [M+H-HCl] ⁺ .

Step 3: Compound ( 2R , 4S )-(6-(methyl(p-tolyl)aminocarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropyl) Synthesis of methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R , 4S )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride (253 mg, 0.42 mmol) was dissolved in dichloromethane (8 mL), cooled in an ice bath, N , N - Diisopropylethylamine (269 mg, 2.08 mmol) and acetyl chloride (82 mg, 1.05 mmol) were stirred at room temperature for 4 h to stop the reaction, water (30 mL) was added and stirred for 2 min, the organic phase was separated, and the aqueous phase was Dichloromethane extraction (5 mL × 2), combined organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 23/1 ) to give a white solid (184 mg, 72% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.50 – 7.64 (m, 1H), 7.27 – 7.38 (m, 1H), 7.20 – 7.27 (m, 1H), 7.08 – 7.13 (m, 1H) , 6.86 – 7.05 (m, 4H), 6.82 (s, 1H), 6.80 (d, J = 3.9 Hz, 1H), 6.60 (t, J _FH = 75.5 Hz, 1H), 5.01 – 5.22 (m, 2H) , 4.53 – 4.57 (m, 1H), 3.92 – 3.97 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.61 (t, J = 10.4 Hz, 1H), 3.46 (s, 3H), 3.37 – 3.45 (m, 1H), 2.66 – 2.72 (m, 1H), 2.25 (s, 3H), 2.11 (s, 3H), 2.04 – 2.09 (m, 1H), 1.24 – 1.34 (m, 1H), 0.63 – 0.67 (m, 2H), 0.34 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 608.30 [M+H] ⁺ .

Example 153: (3-indol-5-yl) methyl (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (di Fluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2-carboxylic acid (200 mg, 0.54 mmol, Example 151, step 5), 6-(hydroxymethyl)isoindol-1-one (221 mg, 1.35 mmol) and N -hydroxy-7-azabenzotriazole (146 mg , 1.08 mmol) was dissolved in dry DMF (8 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (311 mg, 1.62 mmol) was added, N , N -Diisopropylethylamine (279 mg, 2.16 mmol), reacted at room temperature for 11 h, concentrated under reduced pressure to remove the solvent, added water (40 mL), extracted with ethyl acetate (25 mL × 2), the organic phase was washed with anhydrous sulfuric acid It was dried over sodium, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: DCM/MeOH (v/v) = 17/1) to obtain a white solid (176 mg, yield 63%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.85 (s, 1H), 7.59 (d, J = 6.3 Hz, 1H), 7.47 (d, J = 5.7 Hz, 1H), 7.14 (br. s, 1H), 7.10 (d, J = 6.7 Hz, 1H), 6.80 (s, 1H), 6.72 – 6.80 (m, 1H), 6.59 (t, J _FH = 75.7 Hz, 1H), 5.29 (s, 2H), 4.49 – 4.59 (m, 1H), 4.45 (s, 2H), 3.89 – 3.99 (m, 1H), 3.85 (d, J = 4.3 Hz, 2H), 3.55 – 3.66 (m, 1H), 3.35 – 3.48 (m, 1H), 2.60 – 2.74 (m, 1H), 2.12 (s, 3H), 1.99 – 2.08 (m, 1H), 1.25 – 1.33 (m, 1H), 0.58– 0.69 (m, 2H) , 0.27 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 515.20 [M+H] ⁺ .

Embodiment 154 cases of: (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) - N - ((3 -oxoisoindolin-5-yl)methyl)pyrrolidine-2-carboxamide

Compound (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2-carboxylic acid (120 mg, 0.32 mmol, Example 151 step 5), 6-(aminomethyl)isoindol-1-one (58 mg, 0.36 mmol) and N -hydroxy-7-azabenzotriazole (89 mg , 0.65 mmol) was dissolved in dry DMF (4 mL) and dichloromethane (2 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg, 0.98 mmol), N , N -diisopropylethylamine (167 mg, 1.29 mmol) was added, the reaction was carried out at room temperature for 14 h, concentrated under reduced pressure to remove the solvent, added water (20 mL), and extracted with ethyl acetate (15 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 15/1) to obtain a white solid (113 mg, yield 68%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.42 (br.s, 1H), 7.84 (br.s, 1H), 7.45 – 7.56 (m, 2H), 7.25 – 7.34 (m, 1H) , 7.12 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.61 (t, J _FH = 75.7 Hz, 1H), 4.93 – 4.99 (m , 1H), 4.62 – 4.74 (m, 1H), 4.10 – 4.20 (m, 1H), 3.99 – 4.07 (m, 1H), 3.89 – 3.97 (m, 2H), 3.88 (d, J = 6.8 Hz, 2H ), 3.62 – 3.74 (m, 1H), 3.28 – 3.41 (m, 1H), 2.59 – 2.69 (m, 1H), 2.29 – 2.44 (m, 1H), 2.15 (s, 3H), 1.21 – 1.36 (m , 1H), 0.59 – 0.69 (m, 2H), 0.31 – 0.42 (m, 2H).

MS (ESI, pos.ion) m/z: 514.20 [M+H] ⁺ .

Example 155: (2 R, 4 S ) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) - N - ((1 -oxoisoindolin-5-yl)methyl)pyrrolidine-2-carboxamide

Compound (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2-carboxylic acid (120 mg, 0.32 mmol, Example 151, step 5), 5-(aminomethyl)isoindol-1-one (52 mg, 0.32 mmol) and N -hydroxy-7-azabenzotriazole (89 mg , 0.65 mmol) was dissolved in dry DMF (8 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg, 0.98 mmol) was added, N , N -Diisopropylethylamine (167 mg, 1.29 mmol), reacted at room temperature for 18 h, concentrated under reduced pressure to remove the solvent, added water (20 mL), extracted with ethyl acetate (15 mL × 2), the organic phase was washed with anhydrous sulfuric acid It was dried over sodium, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: DCM/MeOH (v/v) = 15/1) to obtain a white solid (70 mg, yield 49%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.10 (br.s, 1H), 7.78 (br.s, 1H), 7.38 – 7.44 (m, 1H), 7.33 (s, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.61 (t, J _FH = 75.6 Hz, 1H), 4.70 – 4.88 (m, 2H), 4.08 – 4.23 (m, 1H), 4.19 (s, 2H), 3.90 – 3.97 (m, 1H), 3.87 (d, J = 6.8 Hz, 2H) , 3.65 – 3.73 (m, 1H), 3.27 – 3.42 (m, 1H), 2.56 – 2.68 (m, 1H), 2.34 – 2.45 (m, 1H), 2.15 (s, 3H), 1.21 – 1.36 (m, 1H), 0.59 – 0.69 (m, 2H), 0.29 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 514.20 [M+H] ⁺ .

Example 156: ( 2R , 4R )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropyl) methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Compound ( 2R , 4R )-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3- Synthesis of (cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

The compound ( 2R , 4R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (900 mg, 2.11 mmol, Example 150, step 5), 6-(hydroxymethyl) -N -methyl- N- (p-methylphenyl)pyridinamide (50 mg, 0.34 mmol) and 1-hydroxyl Benzotriazole (426 mg, 3.15 mmol) was dissolved in dry DMF (8 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (605 mg, 3.16 mmol), N -methylmorpholine (426 mg, 4.21 mmol) was added to the ice bath, the reaction was carried out at room temperature for 10 h, water (130 mL) was added, extracted with ethyl acetate (25 mL × 3), the organic phases were combined, It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: DCM/EtOAc (v/v) = 10/1) to obtain a light brown solid (983 mg, yield 70%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.49 – 7.61 (m, 1H), 7.13 – 7.32 (m, 2H), 7.09 (d, J = 7.8 Hz, 1H), 6.86 – 7.01 (m , 4H), 6.76 – 6.81 (m, 2H), 6.59 (t, J _FH = 75.6 Hz, 1H), 4.99 – 5.18 (m, 2H), 4.37 – 4.48 (m, 1H), 4.05 – 4.09 (m, 0.5H), 3.92 – 3.96 (m, 0.5H), 3.82 – 3.86 (m, 2H), 3.46 (s, 3H), 3.28 – 3.44 (m, 2H), 2.64 – 2.73 (m, 1H), 2.28 – 2.41 (m, 0.5H), 2.24 (s, 3H), 1.99 – 2.11 (m, 0.5H), 1.37 – 1.45 (m, 9H), 1.22 – 1.33 (m, 1H), 0.61 – 0.67 (m, 2H) ), 0.31 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 666.30 [M+H] ⁺ .

Step 2: Compound ( 2R , 4R )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride

The compound ( 2R , 4R )-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3-(cyclo) Propylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (880 mg, 1.32 mmol) was dissolved in dichloromethane (12 mL) and added A solution of 4 mol/L HCl in 1,4-dioxane (5 mL) was stirred at room temperature for 1 h, and the solvent was removed to obtain a pale yellow solid (817 mg, yield 100%).

Step 3: Compound ( 2R , 4R )-(6-(methyl(p-tolyl)aminocarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropyl) Synthesis of methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound (2 R ,4 R )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4- (Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride (795 mg, 1.32 mmol) was dissolved in dichloromethane (15 mL), cooled in an ice bath, and N , N- Diisopropylethylamine (682 mg, 5.28 mmol) and acetyl chloride (259 mg, 3.30 mmol) were stirred at room temperature for 3 h to stop the reaction, water (20 mL) was added and stirred for 2 min, the organic phase was separated, and the aqueous phase was Dichloromethane extraction (10 mL × 2), combined organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 23/1 ) and preparative purification gave a white solid (614 mg, 77% yield, chiral HPLC purity 2R4R: 23.43%, 2R4S: 75.35%). An additional chiral preparation gave a white solid (83 mg).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.55 – 7.65 (m, 1H), 7.22 – 7.35 (m, 2H), 7.12 – 7.16 (m, 1H), 6.87 – 7.05 (m, 4H) , 6.79 – 6.83 (m, 2H), 6.63 (t, J _FH = 75.6 Hz, 1H), 5.02 – 5.25 (m, 2H), 4.79 (d, J = 8.1 Hz, 0.8H), 4.61 (d, J = 8.4 Hz, 0.2H), 4.05 – 4.09 (m, 1H), 3.86 – 3.90 (m, 2H), 3.63 – 3.72 (m, 1H), 3.49 – 3.53 (m, 1H), 3.47 (s, 3H) , 2.34 – 2.47 (m, 2H), 2.27 (s, 3H), 2.13 (s, 2.5H), 2.04 (s, 0.5H), 1.22 – 1.35 (m, 1H), 0.65 – 0.70 (m, 2H) , 0.35 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 608.25 [M+H] ⁺ .

Example 157: ( 2S , 4S )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropyl) methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

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

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

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

MS (ESI, pos.ion) m/z: 340.10 [MH ₂ O-Boc+2H] ⁺ .

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

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

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

MS (ESI, pos.ion) m/z: 370.10 [MH ₂ O-tBu+2H] ⁺ .

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

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

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 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, pos.ion) m/z: 370.10 [M- t- Bu+2H] ⁺ .

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

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

MS (ESI, pos.ion) m/z: 370.10 [M- t- Bu+2H] ⁺ .

Step 5: Compound ( 2S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid synthesis

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

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

MS (ESI, pos.ion) m/z: 372.05 [M- t- Bu+2H] ⁺ .

Step 6: Compound ( 2S )-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropyl) Synthesis of Methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

The compound ( 2S )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid (840 mg , 1.97 mmol), 6-hydroxymethyl- N -methyl- N -p-tolyl-picolinamide (554 mg, 2.16 mmol) and 1-hydroxybenzotriazole (406 mg, 2.94 mmol) were dissolved in N , N -dimethylformamide (15 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (568 mg, 2.95 mmol) was added in an ice bath ) and N -methylmorpholine (440 uL, 3.90 mmol) and stirred at room temperature for 18 h. Water (100 mL) was added to dilute, the organic phase was extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: 60-90 petroleum ether). /ethyl acetate (v/v) = 3/2) to give a white solid (940 mg, 71.85%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.60 – 7.48 (m, 1H), 7.30 – 7.12 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 7.00 – 6.83 (m , 4H), 6.80 – 6.74 (m, 2H), 6.56 (t, J = 75.7 Hz, 1H), 5.18 – 4.96 (m, 2H), 4.60 – 4.33 (m, 1H), 4.02 – 3.88 (m, 1H) ), 3.86 – 3.78 (m, 2H), 3.53 – 3.45 (m, 1H), 3.42 (s, 3H), 3.40 – 3.29 (m, 1H), 2.42 – 2.26 (m, 2H), 2.22 (s, 3H) ), 1.43 (s, 5H), 1.36 (s, 4H), 1.27 – 1.23 (m, 1H), 0.65 – 0.58 (m, 2H), 0.35 – 0.28 (m, 2H).

MS (ESI, pos.ion) m/z: 666.10 [M+H] ⁺ .

Step 7: Compound ( 2S )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-( Synthesis of difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride

Compound ( 2S )-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy) yl)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (940 mg, 1.41 mmol) was dissolved in dichloromethane (14 mL) and injected with hydrogen chloride in dioxane The solution of the ring solution (3.5 mL, 14 mmol, 4 mol/L) was stirred at room temperature for 3 h. The solvent was removed under reduced pressure to give a yellow foamy solid (850 mg, 99.88%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.28 – 8.05 (m, 1H), 7.86 – 7.69 (m, 2H), 7.25 – 7.11 (m, 2H), 7.11 – 6.95 (m, 4H) , 6.93 – 6.78 (m, 1H), 6.56 (t, J = 75.6 Hz, 1H), 5.90 – 5.56 (m, 1H), 5.19 – 4.82 (m, 1H), 4.09 – 3.93 (m, 1H), 3.93 – 3.80 (m, 2H), 3.80 – 3.70 (m, 1H), 3.66 – 3.62 (m, 1H), 3.62 – 3.56 (m, 1H), 3.44 (s, 3H), 2.85 – 2.67 (m, 1H) , 2.53 – 2.34 (m, 1H), 2.30 – 2.12 (m, 3H), 1.28 – 1.17 (m, 1H), 0.64 – 0.49 (m, 2H), 0.38 – 0.25 (m, 2H).

MS (ESI, pos.ion) m/z: 566.10 [M-HCl+H] ⁺ .

Step 8: Compound ( 2S , 4S )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropyl) Synthesis of methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2S )-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(di Fluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride (850 mg, 1.41 mmol), triethylamine (596 uL, 4.23 mmol) was dissolved in dichloromethane (14 mL) at 0 Acetyl chloride (151 uL, 2.12 mmol) was slowly added dropwise at ℃, stirred at room temperature for 2 h. Dichloromethane (50 mL) was added, the organic phase was washed with saturated brine (30 mL × 3), 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 viscous liquid (690 mg, 80.44%, (2S,4S) :(2S,4R) = 63:23), resolved by chiral preparation to give a white solid (144 mg, 16.78%, (2S,4S) = 100%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.56 (br.s, 1H), 7.31 – 7.17 (m, 2H), 7.11 (d, J = 8.2 Hz, 1H), 7.02 – 6.85 (m , 4H), 6.83 – 6.74 (m, 2H), 6.59 (t, J = 75.6 Hz, 1H), 5.23 – 5.00 (m, 2H), 4.75 (d, J = 8.2 Hz, 1H), 4.10 – 3.99 ( m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.70 – 3.58 (m, 1H), 3.52 – 3.44 (m, 1H), 3.43 (s, 3H), 2.45 – 2.37 (m, 1H) , 2.37 – 2.27 (m, 1H), 2.24 (s, 3H), 2.10 (s, 2.5H), 2.00 (s, 0.5H), 1.28 – 1.24 (m, 1H), 0.68 – 0.59 (m, 2H) , 0.38 – 0.30 (m, 2H).

MS (ESI, pos.ion) m/z: 608.20 [M+H] ⁺ .

Example 158: ( 2S , 4R )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropyl) methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

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

Compound ( 2S )-1-(tert-butyloxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro -1 H - pyrrole-2-carboxylic acid (640 mg, 1.50 mmol, Example 157, step 4) was dissolved in ethanol (31 mL), was added Pd / C (520 mg, 10 % Pd, 55% H 2 O) and tris Ethylamine (319 uL, 2.29 mmol) was removed from the air and stirred at room temperature for 17 h under a hydrogen atmosphere. The reaction solution was filtered through celite to remove the solid, and the filtrate was removed from the solvent under reduced pressure to obtain a colorless transparent liquid (645 mg, yield 100%). Synthetic reference: Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2. J. Med. Chem. 2014, 57, 9042 - 9064 .

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.03 (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 – 3.84 (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), 1.29 – 1.18 (m, 1H), 0.63 – 0.56 (m , 2H), 0.34 – 0.28 (m, 2H).

MS (ESI, pos.ion) m/z: 372.05 [M- t- Bu+2H] ⁺ .

Step 2: Compound ( 2S , 4R )-1-tert-butyl 2-(((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-( Synthesis of Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

The compound ( 2S , 4R )-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid (600 mg, 1.40 mmol), 6-hydroxymethyl- N -methyl- N -p-tolyl-picolinamide (396 mg, 1.55 mmol) and 1-hydroxybenzotriazole (290 mg, 2.10 mmol) ) was dissolved in N , N -dimethylformamide (10 mL), cooled in an ice bath, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added ( 405 mg, 2.10 mmol) and N -methylmorpholine (310 uL, 2.80 mmol), stirred at room temperature for 21 h. Water (50 mL) was added to dilute, the organic phase was extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: 60-90 petroleum ether). /ethyl acetate (v/v) = 3/2) to give a white solid (650.0 mg, 0.98 mmol, 69.55% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) ) 7.62 – 7.47 (m, 1H), 7.32 – 7.22 (m, 1H), 7.19 – 7.06 (m, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.02 – 6.85 (m, 4H), 6.81 – 6.77 (m, 2H), 6.58 (t, J = 75.6 Hz, 1H), 5.19 – 4.97 (m, 2H), 4.49 – 4.33 (m, 1H), 4.08 – 3.89 (m, 1H), 3.85 – 3.82 (m, 2H), 3.45 (s, 3H), 3.42 – 3.35 (m, 1H), 3.35 – 3.27 (m, 1H), 2.73 – 2.62 ( m, 1H), 2.10 – 1.97 (m, 1H), 2.03 (s, 3H), 1.45 (s, 4H), 1.36 (s, 5H), 1.25 – 1.23 (m, 1H), 0.66 – 0.60 (m, 2H), 0.37 – 0.31 (m, 2H).

MS (ESI, pos.ion) m/z: 666.30 [M+H] ⁺ .

Step 3: Compound ( 2S , 4R )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride

Compound ( 2S , 4R )-1-tert-butyl 2-(((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropyl) ylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (11195-2) (600 mg, 0.90 mmol) in dichloromethane (10 mL) Into the solution, a solution of hydrogen chloride in dioxane (2.5 mL, 10.0 mmol, 4 mol/L) was injected, and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to obtain a brown viscous liquid (542 mg, 99.88%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.02 – 7.82 (m, 1H), 7.27 – 7.15 (m, 1H), 7.10 – 6.95 (m, 5H), 6.92 – 6.79 (m, 3H) , 6.57 (t, J = 75.7 Hz, 1H), 5.62 – 5.49 (m, 2H), 4.95 – 4.75 (m, 1H), 3.90 – 3.85 (m, 2H), 3.85 – 3.79 (m, 1H), 3.74 – 3.68 (m, 1H), 3.64 – 3.56 (m, 1H), 3.46 – 3.36 (m, 3H), 2.82 – 2.66 (m, 1H), 2.51 – 2.35 (m, 1H), 2.19 (s, 3H) , 1.26 – 1.20 (m, 1H), 0.61 – 0.53 (m, 2H), 0.35 – 0.25 (m, 2H).

MS (ESI, pos.ion) m/z: 566.15 [M-HCl+H] ⁺ .

Step 4: Compound ( 2S , 4R )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3-(cyclopropyl) Synthesis of methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2S , 4R )-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4 -(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride (500 mg, 0.83 mmol), triethylamine (351 uL, 2.49 mmol) in dichloromethane (8 mL) , Acetyl chloride (89 uL, 1.25 mmol) was slowly added dropwise at 0°C, and stirred at room temperature for 2 h. Dichloromethane (50 mL) was added, and the organic phase was washed with saturated brine (30 mL × 3), washed with anhydrous After drying over sodium sulfate, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 50/1) to obtain a yellow viscous liquid (333 mg, 66.00%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.68 – 7.47 (m, 1H), 7.36 – 7.28 (m, 1H), 7.25 – 7.18 (m, 1H), 7.14 – 7.04 (m, 1H) , 7.03 – 6.84 (m, 4H), 6.81 (s, 1H), 6.79 – 6.75 (m, 1H), 6.58 (t, J = 75.5 Hz, 1H), 5.20 – 5.00 (m, 2H), 4.53 (t , J = 8.5 Hz, 1H), 3.97 – 3.88 (m, 1H), 3.84 (d, J = 6.9 Hz, 2H), 3.60 (t, J = 10.5 Hz, 1H), 3.44 (s, 3H), 3.41 – 3.29 (m, 1H), 2.72 – 2.61 (m, 1H), 2.23 (s, 3H), 2.09 (s, 3H), 2.07 – 2.03 (m, 1H), 1.27 – 1.22 (m, 1H), 0.65 – 0.61 (m, 2H), 0.35 – 0.32 (m, 2H).

MS (ESI, pos.ion) m/z: 608.20 [M+H] ⁺ .

Example 159: (2-Methyl-3-oxoisoindolin-5-yl)methyl( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100 mg, 0.27 mmol, Example 1, step 7), 6-(hydroxymethyl)-2-methylisoindol-1-one (50 mg, 0.28 mmol) was dissolved in dichloromethane (10 mL), N- Hydroxy-7-azabenzotriazole (113 mg, 0.81 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (157 mg) was added in an ice bath , 0.81 mmol) and N , N -diisopropylethylamine (141 mg, 1.09 mmol), react at room temperature for 22 h, add water (10 mL), stir for 5 min, extract with dichloromethane (20 mL × 2), combine The organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 1/1) to obtain a white solid (40 mg , yield 28%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.82 (s, 1H), 7.51 – 7.58 (m, 1H), 7.39 – 7.48 (m, 1H), 7.10 (d, J = 7.9 Hz, 1H ), 6.75 – 6.84 (m, 2H), 6.59 (t, J = 75.6 Hz, 1H), 5.23 – 5.34 (m, 2H), 4.47 – 4.60 (m, 1H), 4.30 – 4.42 (m, 2H), 3.90 – 4.00 (m, 1H), 3.79 – 3.89 (m, 2H), 3.61 (t, J = 10.1 Hz, 1H), 3.34 – 3.51 (m, 1H), 3.15 – 3.29 (m, 3H), 2.59 – 2.74 (m, 1H), 2.12 (s, 2.6H), 1.95 – 2.06 (m, 1H), 1.92 (s, 0.4H), 1.22 – 1.26 (m, 1H), 0.59 – 0.71 (m, 2H), 0.29 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 529.20 [M+H] ⁺ .

Example 160: (1,2-Dimethyl-3-oxoisoindolin-5-yl)methyl( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy) yl)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (100 mg, 0.27 mmol, Example 1, step 7), 6-(hydroxymethyl)-2,3-dimethylisoindol-1-one (50 mg, 0.28 mmol) was dissolved in dichloromethane (10 mL), added N -Hydroxy-7-azabenzotriazole (113 mg, 0.81 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 157 mg, 0.81 mmol) and N , N -diisopropylethylamine (141 mg, 1.09 mmol), react at room temperature for 20 h, add water (10 mL), stir for 5 min, and extract with dichloromethane (20 mL × 2) , after combining the organic phases, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=1/1) to obtain a white solid ( 40 mg, 27%, HPLC purity 84.31%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.80 (s, 1H), 7.52 – 7.59 (m, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.73 – 6.83 (m, 2H), 6.59 (t, J = 75.5 Hz, 1H), 5.22 – 5.30 (m, 2H), 4.49 – 4.58 (m, 1H), 4.39 – 4.48 (m, 1H), 3.89 – 3.97 (m, 1H), 3.80 – 3.89 (m, 2H), 3.57 – 3.65 (m, 1H), 3.35 – 3.46 (m, 1H), 3.11 (s, 2.6H), 3.02 (s , 0.4H), 2.62 – 2.72 (m, 1H), 2.12 (s, 2.6H), 1.97 – 2.08 (m, 1H), 1.92 (s, 0.4H), 1.43 – 1.50 (m, 3H), 1.22 – 1.25 (m, 1H), 0.60 – 0.68 (m, 2H), 0.31 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 543.20 [M+H] ⁺ .

Example 161: ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((2-methyl) -3-oxoisoindolin-5-yl)methyl)pyrrolidine-2-carboxamide

Step 1: Compound ( 2R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((((2-methyl- Synthesis of 3-oxoisoindolin-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate

The compound ( 2R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150 mg, 0.35 mmol), 6-(aminomethyl)-2-methylisoindol-1-one (64 mg, 0.36 mmol, intermediate 13) in N , N' -dimethylformamide ( 6 mL), add N -hydroxy-7-azabenzotriazole (146 mg, 1.05 mmol), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiazepine in an ice bath Imine hydrochloride (203 mg, 1.05 mmol) and N , N -diisopropylethylamine (182 mg, 1.41 mmol), react at room temperature for 6 h, add water (10 mL), stir for 5 min, and extract with dichloromethane (20 mL × 2), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the concentrate by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1 ) to give a white solid (157 mg, 76% yield).

¹ H NMR (600 MHz, CD ₃ OD): δ (ppm) 7.67 – 7.73 (m, 1H), 7.55 – 7.63 (m, 1H), 7.47 – 7.54 (m, 1H), 7.05 – 7.10 (m, 1H) ), 7.03 (s, 1H), 6.85 – 6.90 (m, 1H), 6.71 (t, J = 75.8 Hz, 1H), 4.55 – 4.62 (m, 1H), 4.47 (s, 2H), 4.38 – 4.45 ( m, 1H), 4.26 – 4.35 (m, 1H), 3.94 – 3.99 (m, 1H), 3.90 (d, J = 6.6 Hz, 2H), 3.34 – 3.47 (m, 2H), 3.18 (s, 3H) , 2.59 – 2.69 (m, 1H), 2.03 – 2.06 (m, 1H), 1.47 (s, 3H), 1.34 (s, 6H), 1.22 – 1.28 (m, 1H), 0.58 – 0.65 (m, 2H) , 0.33 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 486.25 [M- Boc +2H] ⁺ .

Step 2: Compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -(((2-methyl-3-oxo Synthesis of isoindolin-5-yl)methyl)pyrrolidine-2-carboxamide hydrochloride

The compound ( 2R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((((2-methyl-3- Oxoisoindolin-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (11204-1) (150 mg, 0.26 mmol) dissolved in dichloromethane (10 mL) solution , 4 mol/L HCl in dioxane solution (5 mL) was added, stirred at room temperature for 50 min, and concentrated under reduced pressure to remove the solvent to obtain a white solid (134 mg, 100%).

¹ H NMR (600 MHz, CD ₃ OD): δ (ppm) 7.69 (s, 1H), 7.51 – 7.58 (m, 2H), 7.10 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 1.5 Hz, 1H), 6.87 – 6.92 (m, 1H), 6.73 (t, J = 75.5 Hz, 1H), 4.57 (d, J = 3.6 Hz, 2H), 4.48 (s, 2H), 4.43 – 4.47 ( m, 1H), 3.90 (d, J = 6.8 Hz, 2H), 3.75 – 3.80 (m, 1H), 3.56 – 3.60 (m, 1H), 3.34 – 3.40 (m, 1H), 3.19 (s, 3H) , 2.83 – 2.90 (m, 1H), 2.09 – 2.17 (m, 1H), 1.24 – 1.29 (m, 1H), 0.60 – 0.66 (m, 2H), 0.34 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 486.75 [M-HCl+H] ⁺ .

Step 3: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -(((2-methyl Synthesis of yl-3-oxoisoindolin-5-yl)methyl)pyrrolidine-2-carboxamide

Compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -(((2-methyl-3-oxoisoindium Doolin-5-yl)methyl)pyrrolidine-2-carboxamide hydrochloride (134 mg, 0.26 mmol) was dissolved in dichloromethane (10 mL) and N , N -diisopropylethylamine was added (167 mg, 1.28 mmol), cooled to 0 °C, added with acetyl chloride (59 mg, 0.76 mmol), stirred at room temperature for 1 h, then stopped the reaction, added water (10 mL) to quench the reaction, and extracted with dichloromethane (40 mL × 2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain a white solid (100 mg) , yield 74%).

¹ H NMR (600 MHz, CD ₃ OD): δ (ppm) 7.66 – 7.70 (m, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.50 – 7.55 (m, 1H), 7.03 – 7.12 ( m, 2H), 6.88 – 6.94 (m, 1H), 6.72 (t, J = 75.7 Hz, 1H), 4.54 – 4.60 (m, 1H), 4.51 (s, 2H), 4.47 (s, 2H), 4.04 – 4.10 (m, 1H), 3.86 – 3.95 (m, 2H), 3.58 – 3.67 (m, 1H), 3.43 – 3.53 (m, 1H), 3.19 (s, 3H), 2.60 – 2.71 (m, 1H) , 2.13 (s, 2.4H), 2.00 – 2.09 (m, 1H), 1.91 (s, 0.6H), 1.23 – 1.28 (m, 1H), 0.58 – 0.66 (m, 2H), 0.32 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 528.20 [M +H] ⁺ .

Example 162: ( 2R )-(2-Methyl-1-oxoisoindolin-5-yl)methyl 1-acetoxy-4-(3-(cyclopropylmethoxy)- 4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: Compound ( 2R )-1-tert-butyl 2-(((2-methyl-1-oxoisoindolin-5-yl)methyl)4-(3-(cyclopropylmethyl) Synthesis of oxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

The compound ( 2R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150 mg, 0.35 mmol, Example 1, step 4), 5-(hydroxymethyl)-2-methylisoindol-1-one (64 mg, 0.36 mmol) in N , N' -dimethylformamide amine (6 mL), N -hydroxy-7-azabenzotriazole (146 mg, 1.05 mmol), and 1-ethyl-3-(3-dimethylaminopropyl) in an ice bath Carbodiimide hydrochloride (203 mg, 1.05 mmol) and N , N -diisopropylethylamine (182 mg, 1.41 mmol), react at room temperature for 6 h, add water (10 mL) and stir for 5 min, dichloride Extracted with methane (20 mL × 2), combined the organic phases, dried the organic phases with anhydrous sodium sulfate, concentrated under reduced pressure, and separated the concentrate by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to give a colorless liquid (130 mg, 63% yield).

¹ H NMR (600 MHz, CDCl ₃ ): δ (ppm) 7.78 – 7.85 (m, 1H), 7.41 – 7.47 (m, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.73 – 6.82 (m , 2H), 6.59 (t, J = 75.6 Hz, 1H), 5.32 – 5.38 (m, 1H), 5.19 – 5.24 (m, 1H), 4.42 – 4.49 (m, 1H), 4.34 – 4.38 (m, 2H) ), 3.90 – 3.97 (m, 1H), 3.83 (t, J = 6.8 Hz, 2H), 3.39 – 3.47 (m, 1H), 3.29 – 3.38 (m, 1H), 3.16 – 3.24 (m, 3H), 2.63 – 2.72 (m, 1H), 1.97 – 2.05 (m, 1H), 1.46 (s, 4H), 1.35 (s, 5H), 1.23 – 1.25 (m, 1H), 0.61 – 0.67 (m, 2H), 0.31 – 0.38 (m, 2H).

MS (ESI, pos.ion) m/z: 531.40 [M- t- Bu+2H] ⁺ .

Step 2: Compound ( 2R )-(2-methyl-1-oxoisoindolin-5-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethyl) Synthesis of oxy)phenyl)pyrrolidine-2-carboxylate hydrochloride

Compound ( 2R )-1-tert-butyl 2-(((2-methyl-1-oxoisoindolin-5-yl)methyl)4-(3-(cyclopropylmethoxy) )-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (120 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL) solution, and 4 mol/L HCl was added The solution in dioxane (5 mL) was stirred at room temperature for 50 min, and concentrated under reduced pressure to remove the solvent to obtain a white solid (107 mg, 100%).

¹ H NMR (600 MHz, CD ₃ OD) : δ (ppm) 7.76 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.10 (d , J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.84 – 6.88 (m, 1H), 6.73 (t, J = 75.6 Hz, 1H), 5.49 (s, 0.5H), 5.43 (s, 1.5 H), 4.65 – 4.70 (m, 1H), 4.50 (s, 2H), 3.90 (d, J = 6.8 Hz, 2H), 3.76 – 3.82 (m, 1H), 3.59 (d, J = 4.6 Hz, 1H) ), 3.37 (t, J = 11.1 Hz, 1H), 3.20 (s, 3H), 2.84 – 2.90 (m, 1H), 2.18 – 2.26 (m, 1H), 1.27 – 1.30 (m, 1H), 0.59 – 0.66 (m, 2H), 0.31 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 487.20 [M-HCl+H] ⁺ .

Step 3: Compound ( 2R )-(2-methyl-1-oxoisoindolin-5-yl)methyl 1-acetoxy-4-(3-(cyclopropylmethoxy)- Synthesis of 4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound ( 2R )-(2-methyl-1-oxoisoindolin-5-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) )phenyl)pyrrolidine-2-carboxylate hydrochloride (107 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL), N , N -diisopropylethylamine (133 mg, 1.03 mmol) was added ), cooled to 0 °C, acetyl chloride (48 mg, 0.60 mmol) was added, the reaction was stopped after stirring at room temperature for 1 h, water (10 mL) was added, extracted with dichloromethane (40 mL × 2), the organic phase was washed with anhydrous sulfuric acid It was dried over sodium, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain a white solid (70 mg, yield 65%).

¹ H NMR (600 MHz, CD ₃ OD): δ (ppm) 7.74 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.08 (d , J = 8.2 Hz, 1H), 7.01 (s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.72 (t, J = 75.6 Hz, 1H), 5.22 – 5.37 (m, 2H), 4.52 – 4.57 (m, 1H), 4.49 (s, 2H), 4.07 – 4.13 (m, 1H), 3.89 (d, J = 6.9 Hz, 2H), 3.61 (t, J = 10.4 Hz, 1H), 3.49 – 3.58 (m, 1H), 3.19 (s, 3H), 2.69 – 2.77 (m, 1H), 2.13 (s, 2.5H), 1.97 – 2.06 (m, 1H), 1.94 (s, 0.5H), 1.22 – 1.28 (m, 1H), 0.58 – 0.65 (m, 2H), 0.32 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 529.20 [M +H] ⁺ .

Example 163: ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((2-methyl) -1-oxoisoindolin-5-yl)methyl)pyrrolidine-2-carboxamide

Step 1: Compound ( 2R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((2-methyl-1 -Synthesis of oxoisoindolin-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate

The compound ( 2R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (150 mg, 0.35 mmol, Example 1, step 4), 5-(aminomethyl)-2-methylisoindol-1-one (64 mg, 0.36 mmol, intermediate 14) in N , N' -di In methylformamide (6 mL), N -hydroxy-7-azabenzotriazole (146 mg, 1.05 mmol) was added, and 1-ethyl-3-(3-dimethylene) was added in an ice bath Aminopropyl)carbodiimide hydrochloride (203 mg, 1.05 mmol) and N , N -diisopropylethylamine (182 mg, 1.41 mmol), react at room temperature for 6 h, add water (10 mL) and stir for 5 min, extracted with dichloromethane (20 mL × 2), combined the organic phases, dried the organic phases with anhydrous sodium sulfate, concentrated under reduced pressure, and separated the concentrate by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v /v) = 1/4) to give a white solid (100 mg, 49% yield).

¹ H NMR (600 MHz, CD ₃ OD): δ (ppm) 7.66 – 7.73 (m, 1H), 7.50 – 7.59 (m, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.86 – 6.92 (m, 1H), 6.71 (t, J = 75.7 Hz, 1H), 4.54 – 4.61 (m, 2H), 4.47 (s, 2H) ), 4.28 – 4.38 (m, 1H), 3.94 – 4.01 (m, 1H), 3.90 (d, J = 6.8 Hz, 2H), 3.35 – 3.49 (m, 2H), 3.18 (s, 3H), 2.59 – 2.69 (m, 1H), 1.99 – 2.07 (m, 1H), 1.49 (s, 3H), 1.34 (s, 6H), 1.23 – 1.28 (m, 1H), 0.57 – 0.67 (m, 2H), 0.31 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 586.25 [M+H] ⁺ .

Step 2: Compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((2-methyl-1-oxoiso Synthesis of indolin-5-yl)methyl)pyrrolidine-2-carboxamide hydrochloride

The compound ( 2R )-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((2-methyl-1-oxo Isoindolin-5-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate (100 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL) solution, added 4 mol/L A solution of HCl in dioxane (5 mL) was stirred at room temperature for 50 min, and concentrated under reduced pressure to remove the solvent to obtain a white solid (90 mg, 100%).

¹ H NMR (600 MHz, CD ₃ OD): δ (ppm) 7.74 (d, J = 7.8 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.13 (d , J = 8.2 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 6.89 – 6.93 (m, 1H), 6.76 (t, J = 75.5 Hz, 1H), 4.57 – 4.62 (m, 2H) , 4.50 (s, 2H), 4.44 – 4.48 (m, 1H), 3.90 – 3.94 (m, 2H), 3.75 – 3.78 (m, 1H), 3.58 – 3.62 (m, 1H), 3.36 – 3.43 (m, 1H), 3.21 (s, 3H), 2.85 – 2.91 (m, 1H), 2.09 – 2.16 (m, 1H), 1.26 – 1.29 (m, 1H), 0.61 – 0.69 (m, 2H), 0.34 – 0.41 ( m, 2H).

MS (ESI, pos.ion) m/z: 486.35 [M-HCl+H] ⁺ .

Step 3: Compound ( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((2-methyl) Synthesis of -1-oxoisoindolin-5-yl)methyl)pyrrolidine-2-carboxamide

Compound ( 2R )-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) -N -((2-methyl-1-oxoisoindole) -5-yl)methyl)pyrrolidine-2-carboxamide hydrochloride (90 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL) and N , N -diisopropylethylamine (113 mg, 0.87 mmol), cooled to 0 °C, added acetyl chloride (44 mg, 0.56 mmol), stirred at room temperature for 1 h, then stopped the reaction, added water (10 mL), extracted with dichloromethane (40 mL × 2), organic The phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 20/1) to obtain a white solid (75 mg, yield 82%) ).

¹ H NMR (600 MHz, CD ₃ OD): δ (ppm) 7.68 – 7.73 (m, 1H), 7.55 (s, 1H), 7.44 – 7.49 (m, 1H), 7.04 – 7.12 (m, 2H), 6.89 – 6.93 (m, 1H), 6.73 (t, J = 75.7 Hz, 1H), 4.57 – 4.65 (m, 1H), 4.48 (s, 2H), 4.47 (s, 1H), 4.43 – 4.46 (m, 1H), 4.06 – 4.12 (m, 1H), 3.85 – 3.94 (m, 2H), 3.63 (t, J = 10.6 Hz, 1H), 3.44 – 3.53 (m, 1H), 3.18 (s, 3H), 2.62 – 2.70 (m, 1H), 2.14 (s, 3H), 2.02 – 2.09 (m, 1H), 1.25 – 1.29 (m, 1H), 0.59 – 0.66 (m, 2H), 0.33 – 0.39 (m, 2H) .

MS (ESI, pos.ion) m/z: 528.40 [M +H] ⁺ .

Example 164: ( 2R )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-( Difluoromethoxy)phenyl)-1-carboxypyrrolidine-2-carboxylate

Step 1: Compound ( 2R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid Synthesis

The compound ( 2R )-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate The acid ester (2.4 g, 5.4 mmol, step 4 of Example 1) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and water (10 mL), and then lithium hydroxide monohydrate (688 mg, 16.4 mmol) was added, and the mixture was dissolved at room temperature. The reaction was stopped after 5 h, hydrochloric acid was added to adjust the pH of the solution to 4, tetrahydrofuran was removed under reduced pressure, extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain a colorless viscous solid (2.3 g, yielded rate 99%).

¹ H NMR (400 MHz, CD ₃ OD): δ (ppm) 7.10 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.73 (t , J _FH = 75.5 Hz, 1H), 4.31 – 4.37 (m, 1H), 3.92 – 3.99 (m, 1H), 3.92 (d, J = 6.9 Hz, 2H), 3.35 – 3.47 (m, 2H), 2.69 – 2.76 (m, 1H), 1.97 – 2.09 (m, 1H), 1.46 – 1.49 (m, 9H), 1.24 – 1.34 (m, 1H), 0.62 – 0.66 (m, 2H), 0.37 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 450.20 [M+Na] ⁺ .

Step 2: Compound ( 2R )-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropyl) Synthesis of methoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

The compound ( 2R )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (1.10 g, 2.60 mmol) and 6-(hydroxymethyl) -N -methyl- N- (p-methylphenyl)pyridinamide (690 mg, 0.70 mmol) were dissolved in dichloromethane (30 mL) and added N -Hydroxy-7-azabenzotriazole (700 mg, 5.14 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.50 g, 7.80 mmol) ), N , N -diisopropylethylamine (1.3 g, 10.0 mmol) was added under ice bath, the reaction was carried out at room temperature for 12 h, water (30 mL) was added, extracted with dichloromethane (10 mL×2), the organic phase was It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) = 2/1) to obtain a white viscous solid (1.1 g, 62%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.49 – 7.61 (m, 1H), 7.13 – 7.32 (m, 2H), 7.09 (d, J = 7.9 Hz, 1H), 6.86 – 7.03 (m , 4H), 6.76 – 6.81 (m, 2H), 6.59 (t, J _FH = 75.6 Hz, 1H), 4.99 – 5.18 (m, 2H), 4.37 – 4.48 (m, 1H), 4.05 – 4.09 (m, 0.5H), 3.92 – 3.96 (m, 0.5H), 3.82 – 3.86 (m, 2H), 3.46 (s, 3H), 3.28 – 3.44 (m, 2H), 2.63 – 2.75 (m, 1H), 2.25 ( s, 3H), 1.99 – 2.10 (m, 1H), 1.37 – 1.45 (m, 9H), 1.22 – 1.33 (m, 1H), 0.61 – 0.67 (m, 2H), 0.32 – 0.37 (m, 2H).

MS (ESI, pos.ion) m/z: 666.30 [M+H] ⁺ .

Step 3: Compound ( 2R )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-( Synthesis of difluoromethoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride

Compound ( 2R )-1-tert-butyl 2-((6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethyl) oxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (1.1 g, 2.70 mmol) was dissolved in dichloromethane (15 mL) solution, and 4 mol/ L HCl in ethyl acetate (5 mL) was stirred at room temperature for 1.5 h, and the solvent was removed under reduced pressure to give a pale yellow solid (1.0 g, 100%).

¹ H NMR (400 MHz, CD ₃ OD) δ: (ppm) 7.76 – 7.85 (m, 1H), 7.46 – 7.52 (m, 1H), 7.29 – 7.36 (m, 1H), 7.09 – 7.16 (m, 2H) ), 7.00 – 7.08 (m, 4H), 6.94 – 6.97 (m, 1H), 6.75 (t, J _FH = 75.6 Hz, 1H), 5.29 – 5.39 (m, 2H), 4.73 – 4.78 (m, 1H) , 3.95 (d, J = 6.8 Hz, 2H), 3.82 – 3.87 (m, 1H), 3.71 – 3.78 (m, 1H), 3.36 – 3.47 (m, 1H), 3.45 (s, 3H), 2.87 – 2.95 (m, 1H), 2.30 – 2.43 (m, 1H), 2.24 (s, 3H), 1.26 – 1.38 (m, 1H), 0.61 – 0.68 (m, 2H), 0.35 – 0.42 (m, 2H).

MS (ESI, pos.ion) m/z: 566.20 [M+H-HCl] ⁺ .

Step 4: Compound ( 2R )-(6-(methyl(p-methylphenyl)carbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4 Synthesis of -(difluoromethoxy)phenyl)-1-carboxypyrrolidine-2-carboxylate

Compound ( 2R )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl4-(3-(cyclopropylmethoxy)-4-(difluoro) Methoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride (100 mg, 0.17 mmol) and N -hydroxy-7-azabenzotriazole (45 mg, 0.33 mmol) in dichloro In methane (8 mL), formic acid (45 mg, 0.98 mmol) was added, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (127 mg, 0.66 mmol) was added under ice bath ) and N , N -diisopropylethylamine (306 mg, 2.37 mmol), reacted at room temperature for 2 h, added water (20 mL), stirred for 2 min, extracted with dichloromethane (15 mL × 2), the organic phase was washed with anhydrous It was dried over sodium sulfate, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 15/1) to obtain a white viscous solid (73 mg, yield 74%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.35 (s, 1H), 7.55 – 7.63 (m, 1H), 7.23 – 7.33 (m, 1H), 7.12 – 7.16 (m, 1H), 6.89 – 7.04 (m, 4H), 6.79 – 6.84 (m, 2H), 6.49 – 6.75 (m, 1H), 5.07 – 5.22 (m, 2H), 4.57 – 4.65 (m, 1H), 4.26 – 4.31 (m, 0.2H), 4.06 – 4.09 (m, 0.8H), 3.86 – 3.89 (m, 2H), 3.60 – 3.64 (m, 1H), 3.49 (s, 3H), 3.36 – 3.41 (m, 1H), 2.77 – 2.86 (m, 1H), 2.27 (s, 3H), 2.11 – 2.17 (m, 1H), 1.28 – 1.36 (m, 1H), 0.66 – 0.69 (m, 2H), 0.36 – 0.40 (m, 2H).

MS (ESI, pos.ion) m/z: 594.20 [M+H] ⁺ .

Example 165: 2-(( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl ) isoindoline-5-carboxamide

Step 1: Compound 2-(( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl ) Synthesis of methyl isoindole-5-carboxylate

Compound ( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (300 mg, 0.81 mmol, Example 1, step 7) and methyl isoindole-5-carboxylate (220 mg, 0.89 mmol) were dissolved in DMF (8 mL) and N -hydroxy-7-azabenzotriazole ( 221 mg, 1.62 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (467 mg, 2.44 mmol), N , N -diisopropyl was added under ice bath Ethylamine (419 mg, 3.24 mmol), reacted at room temperature for 5 h, added water (20 mL), extracted with ethyl acetate (5 mL×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel Column chromatography (eluent: DCM/MeOH (v/v) = 35/1) gave a light brown solid (397 mg, 93% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.95 – 8.02 (m, 2H), 7.32 – 7.39 (m, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H) ), 6.87 – 6.90 (m, 1H), 6.63 (t, J _FH = 75.6 Hz, 1H), 5.41 (t, J = 13.8 Hz, 1H), 4.75 – 5.01 (m, 4H), 3.93 – 3.99 (m , 1H), 3.95 (s, 3H), 3.89 (d, J = 6.9 Hz, 2H), 3.76 (t, J = 10.7 Hz, 1H), 3.38 – 3.50 (m, 1H), 2.58 – 2.67 (m, 1H), 2.22 – 2.35 (m, 1H), 2.14 (s, 3H), 1.28 – 1.35 (m, 1H), 0.64 – 0.69 (m, 2H), 0.35 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 529.15 [M+H] ⁺ .

Step 2: Compound 2-(( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl ) Synthesis of isoindoline-5-carboxylic acid

The compound 2-(( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl)iso Methyl indole-5-carboxylate (11208-1) (340 mg, 0.64 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL), and lithium hydroxide monohydrate (135 mg, 3.22 mL) was added. mmol), the reaction was stopped after 30 min at 50 °C, hydrochloric acid was added to adjust the pH of the solution to 2, and then extracted with ethyl acetate (10 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the solvent was removed to obtain a white solid (309 mg, 93 %).

¹ H NMR (600 MHz, CD ₃ OD): δ (ppm) 8.03 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.13 (s , 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.95 – 6.96 (m, 1H), 6.75 (t, J _FH = 75.7 Hz, 1H), 5.27 – 5.31 (m, 1H), 5.02 – 5.06 (m, 1H), 4.90 – 4.94 (m, 1H), 4.80 – 4.85 (m, 2H), 4.10 – 4.14 (m, 1H), 3.92 – 3.95 (m, 2H), 3.69 (t, J = 10.7 Hz , 1H), 3.53 – 3.60 (m, 1H), 2.75 – 2.80 (m, 1H), 2.14 (s, 3H), 2.05 – 2.13 (m, 1H), 1.29 – 1.36 (m, 1H), 0.64 – 0.67 (m, 2H), 0.38 – 0.41 (m, 2H).

MS (ESI, pos.ion) m/z: 515.15 [M+H] ⁺ .

Step 3: Compound 2-(( 2R )-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl ) Synthesis of isoindoline-5-carboxamide

The compound 2-(( 2R )-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl)iso Indole-5-carboxylic acid (90 mg, 0.17 mmol) and ammonium chloride (930 mg, 1.74 mmol) were dissolved in dry DMF (5 mL) and N -hydroxy-7-azabenzotriazole ( 35 mg, 0.26 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (467 mg, 2.44 mmol), N , N -diisopropyl was added under ice bath Ethylamine (134 mg, 0.70 mmol) was reacted at room temperature for 17 h, concentrated under reduced pressure, added water (40 mL), stirred for 2 min, extracted with ethyl acetate (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the mixture was dried under reduced pressure. After concentration, the residue was subjected to silica gel column chromatography (eluent: DCM/MeOH (v/v) = 8/1) to obtain a white solid (78 mg, 87%, HPLC purity 98.12%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.21 – 7.79 (m, 2H), 7.30 – 7.34 (m, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.92 (s, 1H) ), 6.88 (d, J = 8.1 Hz, 1H), 6.63 (t, J _FH = 75.6 Hz, 1H), 5.37 (t, J = 15.2 Hz, 1H), 4.91 – 4.96 (m, 1H), 4.83 – 4.88 (m, 1H), 4.74 – 4.79 (m, 2H), 3.96 – 3.99 (m, 1H), 3.89 (d, J = 6.9 Hz, 2H), 3.73 (t, J = 10.6 Hz, 1H), 3.40 – 3.48 (m, 1H), 2.59 – 2.66 (m, 1H), 2.22 – 2.30 (m, 1H), 2.13 (s, 3H), 1.28 – 1.32 (m, 1H), 0.65– 0.68 (m, 2H) , 0.36 – 0.39 (m, 2H).

MS (ESI, pos.ion) m/z: 514.20 [M+H] ⁺ .

Example 166: ( 2R , 4S )-(6-(p-tolylaminocarboxy)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropylmethoxy) )-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: ( 2R , 4S )-1-tert-butyl 2-((6-(p-tolylcarbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethyl) Synthesis of oxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

Compound (2 R , 4 S )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- carboxylic acid (400 mg, 0.94 mmol, Example 151, step 1), 6- (hydroxymethyl) - N - (p-tolyl) Amides picolinic acid (280 mg, 1.2 mmol) and 1-hydroxybenzotriazole ( 189 mg, 1.4 mmol) was dissolved in N , N -dimethylformamide (10 mL) solution, cooled at 0 °C, and then added 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide (EDCI) (360 mg, 1.9 mmol), N-methylmorpholine (NMM) (190 mg, 1.9 mmol), transferred to room temperature and stirred for 18 h. Water (50 mL) was added to stop the reaction, the organic phase was extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/EtOAc (v/v)=4/1) to give the product as a light brown oil (320 mg, 52.47 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.85 (d, J =24.1 Hz, 1H), 8.24 (dd, J = 14.0, 7.7 Hz, 1H), 8.02 – 7.87 (m, 1H), 7.69 – 7.51 ( m, 3H), 7.18 (dd, J = 8.6, 3.1 Hz, 2H), 7.07 (dd, J = 8.0, 5.5 Hz, 1H), 6.83 – 6.76 (m, 2H), 6.76 – 6.37 (m, 1H) , 5.52 – 5.27 (m, 2H), 4.60 – 4.43 (m, 1H), 4.13 (m, 1H), 3.82 (t, J = 7.2 Hz, 2H), 3.51 – 3.30 (m, 2H), 2.81 – 2.68 (m, 1H), 2.35 (s, 3H), 2.18 – 2.00 (m, 1H), 1.43 (d, J = 22.5Hz, 9H), 1.30-1.22 (m, 1H), 0.67-0.61 (m, 2H) ), 0.36-0.32 (m, 2H).

MS (ESI, pos.ion) m/z: 652.30 [M+H] ⁺ .

Step 2: ( 2R , 4S )-(6-(p-tolylcarbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoro) Synthesis of Methoxy)phenyl)pyrrolidine-2-carboxylate hydrochloride

Compound (2 R , 4 S )-1-tert-butyl 2-((6-(p-tolylcarbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethoxy) yl)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (320 mg, 0.49 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of 1,4 - Dioxane hydrochloric acid solution (1.5 mL, 6.0 mmol), and the reaction was stirred at room temperature for 1 h. The reaction was stopped, after concentration under reduced pressure once, dichloromethane solution (20 mL) was added to dissolve, and concentrated under reduced pressure again to obtain a light brown oily crude product (340 mg, 100.00%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (d, J = 7.7 Hz, 1H), 8.09 (t, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.86 (dd, J = 8.2, 2.1 Hz, 1H), 6.72 (t, J = 75.5 Hz, 1H), 5.66 – 5.44 (m, 2H), 3.90 – 3.84 (m, 2H), 3.82 – 3.71 (m, 2H), 3.64 – 3.58 (m, 1H), 3.39 (t, J = 11.0 Hz, 1H), 3.05-2.96 (m, 1H), 2.88 (s, 3H), 2.37-2.29 (m, 1H) ), 1.32-1.22 (m, 1H), 0.69 – 0.59 (m, 2H), 0.38-0.34 (m, 2H).

MS (ESI, pos.ion) m/z: 552.25 [M+H] ⁺ .

Step 3: ( 2R , 4S )-(6-(p-tolylaminocarboxy)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropylmethoxy) Synthesis of -4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound (2 R , 4 S )-(6-(p-tolylcarbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethyl) Oxy)phenyl)pyrrolidine-2-carboxylate hydrochloride (320 mg, 0.58 mmol) was dissolved in dichloromethane (8.0 mL) solution, cooled at 0 °C, added with N , N -diisopropyl Ethylethylamine (DIPEA) (340 mL, 2.6 mmol) and acetyl chloride (114 mg, 1.45 mmol) were transferred to room temperature and stirred for 3 h. Water (25 mL) was added to stop the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane (25 mL × 2), the organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent). : petroleum ether/EtOAc (v/v) = 3/7) to give a white viscous solid (150 mg, 41.40 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.97 (s, 1H), 8.23 (d, J = 7.7 Hz, 1H), 7.93 (t, J = 7.8 Hz, 1H), 7.67 (d, J = 8.4 Hz , 2H), 7.62 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 1H), 6.84 – 6.78 (m, 2H), 6.60 (t, J = 75.5 Hz, 1H), 5.50 (d, J = 13.7 Hz, 1H), 5.33 (d, J = 13.6 Hz, 1H), 4.66 – 4.59 (m, 1H), 4.01 – 3.93 (m, 1H), 3.84 (d, J = 6.9 Hz, 2H), 3.64 (t, J = 10.4 Hz, 1H), 3.52 – 3.40 (m, 1H), 2.78 – 2.69 (m, 1H), 2.34 (s, 3H) ), 2.17 – 2.07 (m, 1H), 2.12 (s, 3H), 1.32 – 1.22 (m, 1H), 0.69 – 0.61 (m, 2H), 0.41-0.33 (m, 2H).

MS (ESI, pos.ion) m/z: 593.05 [M] ⁺ .

Example 167: ( 2R , 4S )-(6-(methylaminocarboxy)pyridin-2-yl)methyl 1-acetoxy-4-(3-(cyclopropylmethoxy) -4-(Difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Step 1: ( 2R , 4S )-1-tert-butyl 2-((6-(methylaminocarboxy)pyridin-2-yl)methyl)4-(3-(cyclopropylmethoxy) Synthesis of yl)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

Compound (2 R , 4 S )-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2- Formic acid (400 mg, 0.94 mmol, Example 151, step 1), 6-(hydroxymethyl) -N -picolinamide (188 mg, 1.1 mmol, intermediate 16), 1-hydroxybenzotriazole (190 mg, 1.4 mmol) was dissolved in N , N -dimethylformamide (10 mL) solution, cooled at 0 °C, and 1-(3-dimethylaminopropyl)-3-ethyl was added Carbodiimide (EDCI) (358 mg, 1.9 mmol), N -methylmorpholine (NMM) (190 mg, 1.9 mmol), transferred to room temperature and stirred for 14 h. After adding water (50 mL), the organic phase was extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/EtOAc ( v/v)=4/1) to give a light brown oil (530 mg, 98.39 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (m, 1H), 7.92 – 7.82 (m, 1H), 7.55 – 7.48 (m, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.81 ( d, J = 10.4 Hz, 2H), 6.61 (t, J = 75.6 Hz, 1H), 5.43 – 5.27 (m, 1H), 4.60 – 4.42 (m, 1H), 4.12 – 3.95 (m, 1H), 3.85 (t, J = 7.8 Hz, 2H), 3.51 – 3.28 (m, 2H), 3.05 – 3.00 (m, 3H), 2.82 – 2.70 (m, 1H), 2.15 – 1.99 (m, 2H), 1.52 – 1.44 (s, 6H), 1.39 (s, 3H), 1.27 – 1.21 (s, 1H), 0.66 – 0.61 (m, 2H), 0.36 – 0.31 (m, 2H).

MS (ESI, pos.ion) m/z: 576.20 [M+H] ⁺ .

Step 2: (2R, 4S)-(6-(Methylaminocarbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) )Phenyl)pyrrolidine-2-carboxylate hydrochloride synthesis

Compound (2 R , 4 S )-1-tert-butyl 2-((6-(methylaminocarbamoyl)pyridin-2-yl)methyl)4-(3-(cyclopropylmethoxy) )-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (530 mg, 0.92 mmol) was dissolved in dichloromethane (5 mL) and 1,4- Dioxane hydrochloric acid solution (2.5 mL, 10.0 mmol) was stirred at room temperature for 1 h. After concentration under reduced pressure once, dichloromethane solution (20 mL) was added to dissolve, and concentrated under reduced pressure again to obtain a light brown oily crude product (435 mg, yield 92.27%)

¹ H NMR (400 MHz, CD ₃ OD) δ 7.97 – 7.90 (m, 1H), 7.90 – 7.84 (m, 2H), 7.06 – 6.99 (m, 1H), 6.95 (s, 1H), 6.83 – 6.77 ( m, 1H), 6.64 (t, J = 75.6 Hz, 1H), 5.38 (d, J = 6.6 Hz, 2H), 3.85 – 3.77 (m, 2H), 3.74 – 3.53 (m, 4H), 3.32 – 3.20 (m, 1H), 2.83 (s, 3H), 2.24 – 2.05 (m, 1H), 1.14 – 1.25 (m, 1H), 0.55 – 0.51 (m, 2H), 0.30 – 0.24 (m, 2H).

MS (ESI, pos.ion) m/z: 476.20 [M+H] ⁺ .

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

Compound (2 R , 4 S )-(6-(methylcarbamoyl)pyridin-2-yl)methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy) yl)phenyl)pyrrolidine-2-carboxylate hydrochloride (435 mg, 0.91 mmol) was dissolved in dichloromethane (8 mL) alkane solution, cooled at 0 °C, and N,N-diisopropyl was added Ethylamine (DIPEA) (550 mL, 4.3 mmol) and acetyl chloride (200 mg, 2.3 mmol) were transferred to room temperature and stirred for 2 h. Water (25 mL) was added to stop the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane (25 mL × 2), the organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent). : dichloromethane/methanol (v/v) = 50/1) to give a light brown oil (133 mg, yield 27.73 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (br.s, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.87 – 6.79 (m, 2H), 6.61 (t, J = 75.5 Hz, 1H), 5.52 (d, J = 13.8 Hz, 1H) , 5.20 (d, J = 13.8 Hz, 1H), 4.65 – 4.61 (m, 1H), 400 – 3.96 (m, 1H), 3.86 (d, J = 6.9 Hz, 2H), 3.65 (t, J = 10.4 Hz, 1H), 3.52 – 3.39 (m, 1H), 3.03 (d, J = 5.0 Hz, 3H), 2.79 – 2.69 (m, 1H), 2.14 (s, 3H), 2.11 – 1.96 (m, 1H) , 1.33 – 1.22 (m, 1H), 0.69 – 0.63 (m, 2H), 0.36 (m, 2H).

MS (ESI, pos.ion) m/z: 518.20 [M+H] ⁺ .

Example 168: 6 - (((( 2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrole Alkyl-2-carbonyl)oxy)methyl)picolinic acid

Step 1: tert-Butyl 6 - ((((2 R , 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl ) Synthesis of pyrrolidine-2-carbonyl)oxy)methyl)picolinate

Compound (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2-carboxylic acid (540 mg, 1.46 mmol, Example 151, step 5) was dissolved in N , N -dimethylamide (15 mL) solvent, followed by the addition of tert-butyl 6-(hydroxymethyl)picolinate (374 mg, 1.79 mmol, intermediate Compound 17), 1-hydroxybenzotriazole (HOBT) (300 mg, 2.22 mmol), transferred to 0 °C, followed by addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiidene Amine (EDCI) (637 mg, 3.32 mmol), N -methylmorpholine (NMM) (370 mg, 3.66 mmol), after adding the starting materials, transfer to room temperature and stir the reaction for 17 h. Water (50 mL) was added to stop the reaction, and the organic phase was extracted with ethyl acetate (20 mL×3). The organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=1/4) to give a light brown oil (590 mg, 71.99% yield).

1H NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 7.8 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.85 – 6.80 (m, 2H), 6.61 (d, J = 75.5 Hz, 1H), 5.56 – 5.33 (m, 2H), 4.64 – 4.57 (m, 1H), 4.01 – 3.91 (m, 1H), 3.88 – 3.82 (m, 2H), 3.63 (t, J = 10.5 Hz, 1H), 3.51 – 3.42 (m, 1H), 2.79 – 2.68 (m, 1H), 2.19 – 2.10 (m , 1H), 2.13 (s, 3H), 1.61 (s, 9H), 1.34 – 1.24 (m, 1H), 0.68 – 0.63 (m, 2H), 0.38 – 0.34 (m, 2H).

MS (ESI, pos.ion) m/z: 561.30 [M+H] ⁺ .

Step 2: 6-((((2R, 4S)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2 Synthesis of -carbonyl)oxy)methyl)picolinic acid

The compound tert-butyl 6 - ((((2 R , 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) Pyrrolidine-2-carbonyloxy)methyl]picolinate (620 mg, 1.11 mmol) was dissolved in dichloromethane (20 mL) solvent, and trifluoroacetic acid (4.59 g, 40.62 mmol) was added dropwise to the solution. The reaction was stirred at room temperature for 11 h. The reaction was stopped and purified by HPLC prep to give a white viscous solid (210 mg, 34.84% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 7.6 Hz, 1H), 7.96 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.14 (d , J = 8.7 Hz, 1H), 6.84 (s, 1H), 6.83 (d, J = 6.4 Hz, 1H), 6.62 (t, J = 75.5 Hz, 1H), 5.57 (d, J = 14.1 Hz, 1H) ), 5.29 (d, J = 8.7 Hz, 1H), 4.66 – 4.59 (m, 1H), 3.99 (t, J = 8.6 Hz, 1H), 3.87 (d, J = 6.9 Hz, 2H), 3.65 (t , J = 10.5 Hz, 1H), 3.54 – 3.43 (m, 1H), 2.79 – 2.69 (m, 1H), 2.19 – 2.09 (m, 1H), 2.16 (s, 3H), 1.35 – 1.21 (m, 1H) ), 0.69 – 0.64 (m, 2H), 0.38 – 0.34 (m, 2H).

MS (ESI, pos.ion) m/z: 505.10 [M+H] ⁺ .

Example 169: ( 2R , 4S )-(6-(methyl(p-tolyl)carbamoyl)pyridin-2-yl)methyl 1-acetoxy-4-(4-(difluoro) Methoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylate

Step 1: 6 - (((( 2 R, 4 S) -1- acetyl-4- (4- (difluoromethoxy) -3-hydroxyphenyl) pyrrolidine-2-carbonyl) oxy ) methyl) picolinic acid synthesis

The compound tert-butyl 6 - ((((2 R , 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) Pyrrolidine-2-carbonyl)oxy)methyl)picolinate (185 mg, 0.33 mmol, Example 168, step 1) was dissolved in dichloromethane (5.5 mL) solvent and zinc bromide (74 mg) was added , 0.33 mmol), and the reaction was stirred at room temperature for 23.5 h. Water (20 mL) was added, stirred for 2 minutes, the organic phase was separated, the aqueous phase was then extracted with dichloromethane solvent (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate for 30 min, and purified by silica gel column chromatography ( Eluent: dichloromethane/methanol (v/v)=10/1) to give a white solid (22 mg, yield 14.80 %)

MS (ESI, pos.ion) m/z: 451.20 [M+H] ⁺ .

Step 2: ( 2R ,4S)-(6-(methyl(p-tolyl)aminocarbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(4-(difluoromethoxy) Synthesis of phenyl)-3-hydroxyphenyl)pyrrolidine-2-carboxylate

Compound 6-((((2 R , 4 S )-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carbonyl)oxy) Methyl)picolinic acid (100 mg, 0.22 mmol), N -methyl-p-methylaniline (40 mg, 0.33 mmol), dissolved in dichloromethane solvent (5 mL), and 1-hydroxybenzotriazine was added oxazole (HOBT) (148 mg, 1.1 mmol), cooled at 0 °C, added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (126 mg, 0.66 mmol) , N , N -diisopropylethylamine (DIPEA) (142 mg, 1.1 mmol). After the addition of the raw materials, the reaction was stirred at room temperature for 7 h. The reaction was stopped by adding water, extracted with dichloromethane (100 mL×2), the organic phase was dried with anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v )=16/1) to obtain a white solid product (40 mg, yield 28.50%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.51 (s, 1H), 7.13 – 7.02 (m, 3H), 7.01 – 6.96 (m, 2H), 6.94 – 6.86 (m, 2H), 6.83 – 6.64 (m , 2H), 6.61 (t, J = 74.7 Hz, 1H), 5.33 (d, J = 13.8 Hz, 1H), 4.97 (d, J = 13.2 Hz, 1H), 4.61 – 4.52 (m, 1H), 3.91 (t, J = 8.8 Hz, 1H), 3.55 – 3.48 (m, 3H), 3.44 – 3.33 (m, 1H), 2.69 – 2.57 (m, 1H), 2.25 (s, 3H), 2.17 – 2.084 (m , 1H), 2.10 (s, 3H), 1.37 – 1.267 (m, 1H).

MS (ESI, pos.ion) m/z: 554.20 [M+H] ⁺ .

Example 170: (6 - ((4-hydroxyphenyl) (methyl) carbamoyl acyl) pyridin-2-yl) methyl (2 R, 4 S) -1- acetyl-4- (3 -(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylate

Compound (2 R, 4 S) -1- acetyl-4- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) pyrrolidine-2-carboxylic acid (300 mg, 0.81 mmol, 151 Example 5 step), 6- (hydroxymethyl) - N - (4- hydroxyphenyl) - N - Amides methylpyridine (250 mg, 0.97 mmol, intermediate 18) and 1 -Hydroxybenzotriazole (130 mg, 0.97 mmol) was dissolved in dry N , N -dimethylformamide (5 ml) solution, 1-(3-dimethylaminopropyl)-3-ethyl was added carbodiimide (EDCI) (190 mg, 0.97 mmol) and N -methylmorpholine (NMM) (120 mg, 1.22 mmol), transferred to room temperature and stirred for 16 h. Water (30 mL) was added to stop the reaction, the organic phase was extracted with ethyl acetate (10 ml × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH/DCM (v/v)=1 /50) to give a white solid (36 mg, 6.98% yield).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.46 (s, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.28 – 7.21 (m, 2H), 7.12 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 7.02 (t, J _FH = 74.9 Hz, 1H), 6.94 – 6.84 (m, 3H), 6.60 – 6.51 (m, 2H), 5.01 (s, 2H), 4.47 – 4.36 (m, 1H), 4.14 – 4.05 (m, 1H), 3.90 (d, J = 6.3 Hz, 2H), 3.58 – 3.40 (m, 2H), 3.28 (s, 3H), 2.75 – 2.65 ( m, 1H), 2.03 (s, 3H), 2.02 – 1.91 (m, 1H), 1.29 – 1.17 (m, 1H), 0.62 – 0.51 (m, 2H), 0.38 – 0.26 (m, 2H).

MS (ESI, pos.ion) m/z: 610.15 [M+H] ⁺ ..

Example 171 : ( 2R , 4S )-(6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3 -Ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylate

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

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

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

MS (ESI, pos.ion) m/z: 211.10 [M+H] ⁺ .

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

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

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

MS (ESI, pos.ion) m/z: 197.15 [M+H] ⁺ .

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

Step 1: At room temperature, add 3-ethoxy-4-methoxybenzoic acid (9.40 g, 47.91 mmol), triethylamine (6.30 g, 62.28 mmol) to a two-necked flask (100 mL) (A bottle) , toluene (50 mL), stirred in an ice bath, slowly added dropwise diphenylphosphoryl azide (14.50 g, 52.70 mmol), and stirred at room temperature for 2 h.

Step 2: Add toluene (50 mL) and benzyl alcohol (5.70 g, 52.70 mmol) to another single-necked bottle (250 mL) (B bottle), heat to 110°C, drop the material from A bottle into B bottle, and drip it. Keep stirring for 2 h. The heating and stirring were stopped, cooled to room temperature, the reaction solution was washed with water (100 mL), then washed with 5% aqueous sodium hydroxide solution (100 mL × 3), dried over anhydrous Na ₂ SO ₄ , and concentrated by rotary evaporation under reduced pressure to obtain a yellow solid . Petroleum ether/ethyl acetate (50 mL, v/v=10/1) was added to the crude product, stirred for 3 h, and filtered to obtain a white solid (11.55 g, yield 80.00%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.44 – 7.31 (m, 5H), 6.85 – 6.72 (m, 2H), 6.59 (s, 1H), 5.19 (s, 2H), 4.08 (d , J = 6.3 Hz, 2H), 3.84 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H).

MS (ESI, pos.ion) m/z: 302.10 [M+H] ⁺ .

Step 4: Synthesis of compound 3-ethoxy-4-methoxyaniline

To the autoclave (1 L) was added benzyl(3-ethoxy-4-methoxyphenyl)carbamate (11.50 g, 38.16 mmol), 10% palladium on carbon (0.61 g, 0.57 mmol), Methanol (40 mL), remove air, pass hydrogen (0.5 MPa), and stir at room temperature for 2 h. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a brown solid (6.38 g, yield 100%)

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.71 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 6.23 (dd, J = 8.4, 2.6 Hz, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.79 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H).

MS (ESI, pos.ion) m/z: 168.20 [M+H] ⁺ .

Step 5: Synthesis of compound 3-ethoxy-4-methoxyiodobenzene

Compound 3-ethoxy-4-methoxyaniline (6.40 g, 38.28 mmol) was dissolved in 1,4-dioxane (30 mL) and water (11 mL), cooled to 0 °C, added Concentrated hydrochloric acid (9.7 mL, 36% aq), stirred evenly, cooled to -15 °C, and a solution of sodium nitrite (2.91 g, 42.11 mmol) and water (7 mL) was added dropwise, and the dropwise temperature was controlled at -15 °C After dropping to -5°C, return 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), and control the dropwise temperature at -15°C to -5°C. After dropping, the temperature was returned to 0 °C and stirred for 2 h. Sodium bisulfite (1.99 g, 19.14 mmol) was added and stirred for 1 h to quench the reaction. Petroleum ether (200 mL) was added to the reaction solution, and the organic phase was washed with water ( 100 mL × 3), dried over anhydrous Na ₂ SO 4 , and concentrated under reduced pressure to obtain a yellow viscous liquid. Silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10/1) was purified to give a white solid (6.24 g, yield 58.62%)

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.21 (dd, J = 8.4, 1.9 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.84 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H).

GC-MS: m/z 278.00 [M] ⁺ .

Step 6: Synthesis of compound 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxazolidine

3-Ethoxy-4-methoxyiodobenzene (1277-6) (6.24 g, 22.44 mmol), pinacol diboronate (5.70 g, 22.44 mmol), potassium acetate (3.30 g, 33.66 mmol) , palladium acetate (0.25 g, 1.12 mmol), 2-dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) (0.82 g, 2.24 mmol) were mixed in N , N -dimethylformamide (36 mL) ), stirred at 80 °C for 6 h under nitrogen protection. Cooled to room temperature, water (100 mL) was added to the reaction solution, the reaction solution was extracted with petroleum ether (100 mL × 3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to obtain a brown liquid. Chromatography (petroleum ether/ethyl acetate (v/v)=10/1) was purified to give a yellow solid (4.85 g, yield: 77.70%)

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.41 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.89 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H), 1.33 (s, 12H).

MS (ESI, pos.ion) m/z: 279.35 [M+H] ⁺ .

Step 7: Compound (R) -1- tert-butyl 2-methyl-4- (3-ethoxy-4-methoxyphenyl) -1 H - pyrrole -1,2 (2 H, 5 H) - Synthesis of Diformate

Compound 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.0 g, 7.19 mmol) , ( R )-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy) 1H -pyrrole- 1,2(2H , 5H )-dicarboxylic acid ester (2.7 g, 7.19 mmol), N -methylmorpholine (1.6 g, 15.82 mmol), dicyclohexyl-[2-(2-methylphenyl)phenyl]phosphine (0.13 g, 0.36 mmol) and Palladium acetate (0.04 g, 0.18 mmol) was mixed with a mixed solution of toluene (10 mL) and water (5 mL), and reacted at 80 °C for 1 h under nitrogen protection. The reaction was stopped and cooled to room temperature. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was separated by silica gel column chromatography (eluent: PE/EtOAc ( v/v ) = 5/1) to give a yellow liquid (1.1 g, 44% yield).

MS (ESI, pos.ion) m/z: 278.18 [M- Boc +2H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 6.93 – 6.88 (m, 2H), 6.85 – 6.81 (m, 1H), 5.94 – 5.89 (m, 1H), 5.18 – 5.08 (m, 1H), 4.66 – 4.47 (m, 2H), 4.14 – 4.07 (m, 2H), 3.88 (s, 3H), 3.75 (d, J = 4.8 Hz, 3H), 1.52 (s, 3H), 1.50 – 1.43 (m, 9H).

Step 8: Compound ( 2R , 4S )-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate synthesis

The compound (R) -1- tert-butyl 2-methyl-4- (3-ethoxy-4-methoxyphenyl) -1 H - pyrrole -1,2 (2 H, 5 H) - two Formate (2.0 g, 5.30 mmol) and palladium on carbon (0.45 g, 5.30 mmol) were dissolved in 35 mL of methanol, and reacted at room temperature for 12 h under a hydrogen atmosphere. The reaction of the raw materials was complete and the reaction was stopped. The palladium carbon was filtered through celite, and the organic phase was concentrated under reduced pressure to obtain a yellow liquid (1.26 g, yield 63%).

MS (ESI, pos.ion) m/z: 280.20 [M- Boc +2H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 6.82 – 6.74 (m, 3H), 4.39 – 4.29 (m, 1H), 4.11 – 4.05 (m, 2H), 4.02 – 4.00 (m, 0.5H) , 3.95 – 3.89 (m, 0.5H), 3.85 (s, 3H), 3.76 (d, J = 7.0 Hz, 3H), 3.44 – 3.37 (m, 1H), 3.33 – 3.24 (m, 1H), 2.66 – 2.57 (m, 1H), 2.07 – 1.96 (m, 1H), 1.50 – 1.44 (m, 6H), 1.43 (s, 6H).

Step 9: Synthesis of Compound (2R , 4S )-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

Compound (2 R , 4 S )-1-tert-butyl 2-methyl 4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (1.2 g , 3.16 mmol) was dissolved in 10 mL of dichloromethane solution, and then hydrochloric acid 1,4-dioxane solution (3.94 mL, 4.01 mol/L) was added, and the reaction was carried out at room temperature for 1.5 h. The reaction of the raw materials was completed and the reaction was stopped. The solvent was removed by distillation under reduced pressure, and the concentrated solution gave a yellow liquid (1.02 g, yield 100%).

MS (ESI, pos.ion) m/z: 280.30 [M+H-HCl] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 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, pos.ion) m/z: 280.30 [M+H-HCl] ⁺ .

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

Compound ( 2R , 4S )-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1.0 g, 3.17 mmol) was dissolved in 20 mL of In the methyl chloride solution, under ice bath conditions, N , N -diisopropylethylamine (1.64 g, 12.68 mmol), acetyl chloride (0.50 g, 6.34 mmol) were added, and the reaction was carried out at room temperature for 1 h, and the reaction of the raw materials was complete. , stop the reaction. Saturated brine was added to quench the reaction, extracted with dichloromethane (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrated solution was subjected to silica gel column separation (eluent: DCM/MeOH (v/v) = 20/1) to give a yellow liquid (0.95 g, 93% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 6.84 – 6.80 (m, 1H), 6.79 – 6.77 (m, 1H), 6.76 – 6.74 (m, 1H), 4.46 (dd, J = 9.7, 7.5 Hz, 1H), 4.08 (q, J = 6.9 Hz, 2H), 3.93 – 3.89 (m, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.59 (t, J = 10.5 Hz, 1H) ), 3.42 – 3.33 (m, 1H), 2.66 – 2.60 (m, 1H), 2.10 (s, 3H), 2.05 – 2.00 (m, 1H), 1.46 (t, J = 7.0 Hz, 3H).

MS (ESI, pos.ion) m/z: 322.20 [M+H] ⁺ .

Step 11: Compound (2 R, 4 S) -1- acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidine-2-carboxylic acid Synthesis of

Compound (2 R, 4 S) -1- acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidine-2-carboxylate was dissolved in tetrahydrofuran (8 mL) and water (4 mL) of mixed solvent, lithium hydroxide (59 mg, 2.48 mmol) was added, and the reaction was carried out under heating at 50 °C for 1.5 h. The reaction of the raw materials was completed, the reaction was stopped, saturated brine (30 mL) was added, pH=3 was adjusted with dilute hydrochloric acid, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow Solid (320 mg, 84% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 6.85 – 6.81 (m, 1H), 6.80 (s, 1H), 6.78 – 6.76 (m, 1H), 4.58 (t, J = 8.6 Hz, 1H) , 4.13 – 4.07 (m, 2H), 3.96 – 3.92 (m, 1H), 3.86 (s, 3H), 3.54 (t, J = 10.6 Hz, 1H), 3.39 – 3.31 (m, 1H), 2.69 – 2.62 (m, 1H), 2.39 – 2.30 (m, 1H), 2.18 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H).

MS (ESI, pos.ion) m/z: 308.15 [M+H] ⁺ .

Step 12: Compound ( 2R , 4S )-(6-((4-((tert-butyldimethylsilyl)oxy)phenyl)(methyl)carbamoyl)pyridin-2-yl ) Synthesis of methyl 1-acetyl-4-(3-ethoxy-4-methoxyphenyl) pyrrolidine-2-carboxylate

Compound (2 R, 4 S) -1- acetyl-4- (3-ethoxy-4-methoxyphenyl) pyrrolidine-2-carboxylic acid (140 mg, 0.44 mmol), N - ( 4-((tert-Butyldimethylsilyl)oxy)phenyl)-6-(hydroxymethyl) -N -picolinamide (150 mg, 0.40 mmol) and 1-hydroxy-7- Azabenzotriazole (110 mg, 0.80 mmol) was dissolved in dichloromethane (20 mL) solution, and 1-(3-dimethylaminopropyl)-3-ethylcarbodie Imine hydrochloride (150 mg, 0.80 mmol) and N , N -diisopropylethylamine (160 mg, 1.20 mmol) were reacted at room temperature for 18 h, the reaction of the raw materials was complete, the reaction was stopped, and saturated common salt was added Water (50 mL), extracted with dichloromethane (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure for silica gel column chromatography (eluent: PE/EtOAc (v/v) = 1/1 ) was separated and purified to obtain pale yellow liquid (200 mg, yield 76%).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.58 – 7.55 (m, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 6.7 Hz, 1H), 6.91 – 6.89 (m, 2H), 6.84 – 6.79 (m, 2H), 6.77 – 6.76 (m, 1H), 6.63 (d, J = 7.9 Hz, 2H), 5.26 – 5.23 (m, 1H), 5.07 – 5.03 (m , 1H), 4.56 – 4.52 (m, 1H), 4.14 – 4.05 (m, 3H), 3.95 – 3.90 (m, 1H), 3.86 (s, 3H), 3.60 (t, J = 10.5 Hz, 1H), 3.46 (s, 3H), 3.40 – 3.37 (m, 1H), 2.70 – 2.64 (m, 1H), 2.11 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H), 0.93 (s, 9H) , 0.13 (s, 6H).

MS (ESI, pos.ion) m/z: 662.20 [M+H] ⁺ .

Step 13: ( 2R , 4S )-(6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3- Synthesis of Ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylate

Compound (2 R , 4 S )-(6-((4-((tert-butyldimethylsilyl)oxy)phenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-Acetyl-4-(3-ethoxy-4-methoxyphenyl)pyrrolidine-2-carboxylate (200 mg, 0.30 mmol) was dissolved in tetrahydrofuran (10 mL) and added with tetrahydrofuran Butylammonium fluoride solution (0.60 mL, 1.0 mmol/L) was reacted at room temperature for 1 h. The reaction of the raw materials was completed, the reaction was stopped, saturated brine (30 mL) was added, extracted with ethyl acetate (20 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure for silica gel column chromatography (eluent: DCM/ MeOH (v/v) = 20/1) was isolated and purified to obtain a white solid (136 mg, 82% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.54 (t, J = 7.7 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.88 – 6.84 (m, 2H), 6.82 – 6.77 (m, 2H), 6.76 – 6.74 (m, 1H), 6.72 – 6.66 (m, 2H), 5.11 – 5.06 (m, 1H), 4.96 – 4.93 (m , 1H), 4.55 (t, J = 8.6 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.96 – 3.91 (m, 1H), 3.85 (s, 3H), 3.62 (t, J = 10.5 Hz, 1H), 3.46 (s, 3H), 3.41 – 3.37 (m, 1H), 2.72 – 2.66 (m, 1H), 2.14 (s, 3H), 2.08 – 2.01 (m, 1H), 1.46 (t , J = 7.0 Hz, 3H).

MS (ESI, pos.ion) m/z: 548.70 [M+H] ⁺ .

Example 172: ( 2R , 4S )-(6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3 -Isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylate

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

The compound 3-hydroxy-4-methoxybenzoic acid methyl ester (5.00 g, 27.45 mmol), isopropyl iodide (7.00 g, 41.17 mmol) and potassium carbonate (11.83 g, 82.35 mmol) were mixed in N , N - dimethylformamide (25 mL), and stirred at 80 °C for 10 h. Ethyl acetate (100 mL) was added for dilution, the organic phase was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow liquid (5.48 g, yield 89.02 %).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.62 (dd, J = 8.5, 1.8 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 4.60 – 4.54 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 1.35 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 225.20 [M+H] ⁺ .

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

Compound 3-isopropoxy-4-methoxybenzoic acid methyl ester (11.05 g, 49.28 mmol), sodium hydroxide (3.94 g, 98.56 mmol), ethanol (30 mL), water (10 mL) were mixed uniformly , and stirred at 50 °C for 2 h. Dilute hydrochloric acid (4 M/L) was added dropwise to adjust pH=1, water (100 mL) was added, stirred (a large amount of solid was precipitated), filtered, and the obtained filter cake was washed with water (50 mL×3), dried in vacuum at 60 °C for 12 h, A white solid (10.36 g, 100 % yield) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.76 (dd, J = 8.5, 1.9 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.66 – 4.60 (m, 1H), 3.93 (s, 3H), 1.40 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 211.15 [M+H] ⁺ .

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

Step 1: at room temperature, add 3-isopropoxy-4-methoxybenzoic acid (10.30 g, 48.99 mmol), triethylamine (6.44 g, 663.69 mmol), toluene (50 ml), placed in an ice bath and stirred, slowly added dropwise diphenylphosphoryl azide (DPPA) (14.83 g, 53.89 mmol), and stirred at room temperature for 2 h.

Step 2: Add toluene (50 ml) and benzyl alcohol (5.83 g, 53.89 mmol) to another three-necked bottle (B bottle), heat to 110 °C, drop the material from bottle A into bottle B, and stir at constant temperature for 2 h after dropping . The heating and stirring were stopped, cooled to room temperature, the reaction solution was washed with water (100 mL), then washed with 5% aqueous sodium hydroxide solution (100 mL×3), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain a yellow solid. Petroleum ether/ethyl acetate (50 mL, v/v = 10:1) was added to the crude product, stirred for 3 h, and filtered to obtain a white solid (11.34 g, yield 73.40 %).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.47 – 7.30 (m, 5H), 7.20 – 7.11 (m, 1H), 6.86 – 6.72 (m, 2H), 6.56 (s, 1H), 5.19 (s, 2H), 3.82 (s, 3H), 1.36 (d, J = 5.9 Hz, 6H).

MS (ESI, pos.ion) m/z: 316.20 [M+H] ⁺ .

Step 4: Synthesis of compound 3-isopropoxy-4-methoxyaniline

To the autoclave was added benzyl(3-isopropoxy-4-methoxyphenyl)carbamate (11.34 g, 35.96 mmol), 10% palladium on carbon (0.51 g, 0.54 mmol), methanol (40 mL), replaced with hydrogen (0.5 MPa), and stirred at room temperature for 2 h. The reaction solution was filtered through celite, and the filtrate was collected and concentrated under reduced pressure to obtain a brown solid (6.52 g, yield 100%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 6.71 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 6.24 (dd, J = 8.4, 2.5 Hz, 1H), 4.49 – 4.43 (p, J = 6.1 Hz, 1H), 3.77 (s, 3H), 1.34 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 182.20 [M+H] ⁺ .

Step 5: Synthesis of compound 3-isopropoxy-4-methoxyiodobenzene

Compound 3-isopropoxy-4-methoxyaniline (6.90 g, 38.07 mmol) was dissolved in 1,4-dioxane (30 mL) and water (11 mL), cooled to 0 °C, Add concentrated hydrochloric acid (9.6 mL, 36% aq), stir well, cool to -15 °C, add a solution of sodium nitrite (2.89 g, 41.88 mmol) and water (7 mL) dropwise, control the dropwise temperature at -15 Between ℃ and -5 ℃, return to -5 ℃ and stir for 30 min after dropping, add a solution of potassium iodide (8.22 g, 49.49 mmol) and water (12 mL), and control the dropwise temperature at -15 ℃ to -5 ℃. After dropping, the temperature was returned to 0 °C and stirred for 2 h. Sodium bisulfite (1.98 g, 19.04 mmol) was added and stirred for 1 h to quench the reaction. Petroleum ether (200 mL) was added to the reaction solution, and the organic phase was washed with water (100 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a yellow viscous liquid. Silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=10/1) was purified to obtain a white solid (7.83 g, yield 70.41 %)

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 7.21 (dd, J = 8.5, 1.9 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H), 6.62 (d, J = 8.5 Hz, 1H), 4.53 – 4.44 (m, 1H), 3.82 (s, 3H), 1.36 (d, J = 6.1 Hz, 6H).

GC-MS: m/z 292.0 [M] ⁺ .

Step 6: Synthesis of compound 2-(3-isopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

3-Isopropoxy-4-methoxyiodobenzene (8.64 g, 26.63 mmol), pinacol diboronate (6.76 g, 26.63 mmol), potassium acetate (39.2 g, 39.95 mmol), palladium acetate ( 0.30 g, 1.33 mmol), 2-dicyclohexylphosphorus-2'-methylbiphenyl (Mephos) (0.97 g, 2.66 mmol) was mixed in N , N -dimethylformamide (48 mL) under nitrogen Stir at 80 °C for 6 h under the protection. Cool to room temperature, add water (100 mL) to the reaction solution, extract the reaction solution with petroleum ether (100 mL×3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a brown liquid, which is passed through a silica gel column layer. It was purified by analysis (eluent: petroleum ether/ethyl acetate (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: Compound (R) -1- tert-butyl 2-methyl-4- (3-isopropoxy-4-methoxy-phenyl) -1 H - pyrrole -1, 2 (2 H, 5 H )-Diformate Synthesis

The compound (R) -1- tert-butyl 2-methyl 4 - ((((trifluoromethyl) sulfonyl acyl) methoxy) -1 H - pyrrole -1, 2 (2 H, 5 H) - Dicarboxylate (5.50 g, 14.65 mmol, Intermediate M ₂ ), 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4,4,5 , 5-tetramethyl-1,3,2-dioxaborolane (4.49 g, 15.38 mmol), palladium acetate (82.23 mg, 0.37 mmol), dicyclohexyl-[2-(2-methyl) phenyl) phenyl] phosphine (267.00 mg, 0.73 mmol), dissolved in toluene (30 mL) solvent, and then added 4-methylmorpholine (3.25 g, 32.08 mmol), water (15 mL), under nitrogen atmosphere Then, it was transferred to 80 °C and stirred for 2 h, cooled to room temperature, added with water (100 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was dried with anhydrous sodium sulfate for 30 min, and passed through a silica gel column layer. Purification (eluent: ethyl acetate/petroleum ether (v/v) = 3/20) gave a brown sticky (5 g, 87.19 % yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 6.96 – 6.90 (m, 2H), 6.85 – 6.82 (m, 1H), 5.93 – 5.87 (m, 1H), 5.17 – 5.08 (m, 1H), 4.66 – 4.46 (m, 3H), 3.85 (s, 3H), 3.74 (d, J = 5.0 Hz, 3H), 1.52 (s, 3H), 1.45 (s, 6H), 1.36 (d, J = 6.1 Hz , 6H).

MS (ESI, pos.ion) m/z: 336.05 [M- t- Bu+2H] ⁺ .

Step 8: Compound ( 2R , 4S )-1-tert-butyl 2-methyl 4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-1,2-dicarboxylate Synthesis

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

The compound ( 2R , 4S )-1-tert-butyl 2-methyl 4-(4-methoxy-3-(propoxy)phenyl)pyrrolidine-1,2-dicarboxylate ( 1.70g, 4.32mmol) was dissolved in dichloromethane (3 mL) solvent, and then hydrogen chloride/1,4-dioxane (9 mL) solution was added. After adding the raw materials, the reaction was stirred at room temperature for 2 h. The reaction was stopped and concentrated under reduced pressure once, then dichloromethane (20 mL) was added to dissolve, and concentrated under reduced pressure again to obtain a 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, pos.ion) m/z: 294.30[M+H-HCl] ⁺ .

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

Compound ( 2R , 4S )-4-(3-isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylate methyl ester hydrochloride (1.7 g, 5.79 mmol) was dissolved in two In a solvent of methyl chloride (10 mL), cooled in an ice bath, ethyldiisopropylamine (DIPEA) (2.99 g, 23.16 mmol) and acetyl chloride (0.91 g, 11.58 mmol) were slowly added sequentially, and the temperature was brought to room temperature. The reaction was stirred for 2 h. The reaction was stopped, the reaction solution was washed with water (50 mL×1), the organic phase was extracted once with dichloromethane (20 mL), the organic phases were combined, washed once with saturated brine (50 mL), the organic phase was separated, and anhydrous sulfuric acid was added to the organic phase. It was dried over sodium for 30 min, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=80%) to obtain a light brown viscous (1.386 g, yield 71.37%)

¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 6.84 – 6.75 (m, 3H), 4.54 – 4.43 (m, 2H), 3.93 – 3.88 (m, 1H), 3.83 (s, 3H), 3.76 ( s, 3H), 3.58 (t, J = 10.5 Hz, 1H), 3.41 – 3.31 (m, 1H), 2.66 – 2.59 (m, 1H), 2.10 (s, 3H), 2.07 – 2.00 (m, 1H) , 1.34 (d, J = 6.1 Hz, 6H).

MS (ESI, pos.ion) m/z: 336.35 [M+H] ⁺ .

Step 11: Compound (2 R, 4 S) -1- acetyl-4- (3-isopropoxy-4-methoxyphenyl) pyrrolidine-2-carboxylic acid

Compound (2 R, 4 S) -1- acetyl-4- (3-isopropoxy-4-methoxyphenyl) pyrrolidine-2-carboxylic acid methyl ester (0.62 g, 1.86 mmol), Hydrate lithium hydroxide (0.16 g, 3.72 mmol) was dissolved in tetrahydrofuran (5 mL) and water (2.5 mL), and stirred at 50 °C for 3 h. Stop the reaction, cool at -5 °C, add dilute hydrochloric acid (0.5 M/L) dropwise, adjust pH=2, add saturated brine (50 mL×2) to wash, separate the organic phase, dry over anhydrous sodium sulfate for 30 min, reduce Concentrated under pressure to give a pale yellow solid (561 mg, 93.85% yield)

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.91 – 6.85 (m, 2H), 6.84 – 6.78 (m, 1H), 4.59 – 4.50 (m, 2H), 4.23 – 4.19 (m, 1H), 4.06 – 4.00 (m, 1H), 3.72 (s, 3H), 3.30 – 3.18 (m, 1H), 2.67 – 2.58 (m, 1H), 2.00 (s, 3H), 1.91 – 1.78 (m, 2H), 1.24 (d, J = 6.0 Hz, 6H).

MS (ESI, pos.ion) m/z: 322.20 [M+H] ⁺ .

Step 12: Compound ( 2R , 4S )-(6-((4-hydroxyphenyl)(methyl)carbamoyl)pyridin-2-yl)methyl 1-acetyl-4-(3 -Synthesis of isopropoxy-4-methoxyphenyl)pyrrolidine-2-carboxylate

Compound (2 R, 4 S) -1- acetyl-4- (4-methoxy-3- (prop-2-yloxy) phenyl) pyrrolidine-2-carboxylic acid (151.04 mg, 0.47 mmol), 6- (hydroxymethyl) - N - (4- hydroxyphenyl) - N - methylpyridine-2carboxamide (145.66 mg, 0.56 mmol), N - (3- dimethylaminopropyl yl) - N '- ethylcarbodiimide hydrochloride (135.15 mg, 0.7 mmol), 1- hydroxybenzotriazole (76.21 mg, 0.56 mmol), 4- methylmorpholine (76.06 mg, 0.75 mmol ), dissolved in dichloromethane (5 mL) solvent, and the reaction was stirred at room temperature for 5 h. The reaction was stopped, water (20 mL) was added, extracted with ethyl acetate (10 mL×2), the organic phase was washed with saturated brine (20 mL) once, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and a silica gel column layer was used. Separation (eluent: methanol/dichloromethane (v/v)=5%) gave a white solid (30 mg, yield 13.06%)

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.46 (s, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.27 – 7.21 (m, 2H), 6.94 – 6.86 (m, 4H), 6.85 – 6.79 (m, 1H), 6.55 (d, J = 8.2 Hz, 2H), 5.09 – 4.95 (m, 2H), 4.57 – 4.49 (m, 1H), 4.43 – 4.35 (m, 1H), 4.09 – 4.02 (m, 1H), 3.72 (s, 3H), 3.29 (s, 3H), 3.50 – 3.40 (m, 2H), 2.03 (s, 3H), 1.99 – 1.85 (m, 2H), 1.22 (d, J = 5.9 Hz, 6H).

MS (ESI, pos.ion) m/z: 562.50 [M+H] ⁺ .

biological test

Biological Example 1: Determination of the Inhibitory Effect of the Compounds of the Invention on PDE4B2 Enzyme

1. Experimental method

The present invention adopts the following methods to conduct biological tests on the compounds of the present invention: (1) Using a BPS production kit (BPS, Cat. No. 60343), according to the instructions provided by the manufacturer, a fluorescence polarization method is used to detect the inhibitory effect of the compounds on PDE4B2 enzyme. (2) The PDE4B2 enzyme concentration was prepared to 83.33 pg/μL, and the final concentration was 27.78 pg/μL; the substrate FAM-Cyclic-3', 5'-AMP concentration was prepared to 300 nM, the final reaction concentration was 100 nM, and the enzyme and The substrate diluents were all used in the kit's own buffer PDE Assay buffer; Binding Agent was 100-fold diluted with the kit's own Binding Agent Diluent for use. The reaction system is shown in Table 1. [Table 1] IC ₅₀ detection system for PDE4B2 enzyme Test sample well Positive control wells Negative control wells Buffer blank control wells PDE4B2 enzyme 5 μL 5 μL 0 μL 0 μL FAM-Cyclic-3', 5'-AMP substrate 5 μL 5 μL 5 μL 0 μL Test sample 5 μL 0 μL 0 μL 0 μL PDE Assay buffer 0 μL 5 μL 10 μL 15 μL Incubate for 1 h at 25°C in a constant temperature shaker box Binding Agent 15 μL 15 μL 15 μL 15 μL 25°C, shaking with constant temperature oscillator for 1 h

A 384-well plate was used for detection. The experiment was set up with test sample wells, positive control wells, negative control wells and blank wells. Each sample was tested for the inhibitory effect on the PDE4B2 enzyme concentration at 10 concentrations by double wells. PDE4B2 enzyme and FAM were used for the detection The -Cyclic-3',5'-AMP substrate reaction well was used as a positive control, the FAM-Cyclic-3',5'-AMP substrate well was used as a negative control, and the buffer well was used as a blank control. After adding the corresponding samples, enzymes, substrates and buffers to each well in the order of Table 1, incubate at 25°C for 1 h, then add 15 μL of the configured Binding Agent to each well, and shake at 25°C for 1 hour. After h, detection was performed at the wavelength of FP485/525 using a PHER Astar FS multifunctional microplate reader (BMG). Graph Pad Prism 5 software was used to plot the inhibitory effects of compounds on PDE4B2 at different concentrations, and IC _{50 was} calculated.

2. Experimental results

According to the above method, the inhibitory effect of the compounds provided in the examples of the present invention on PDE4B2 enzyme was measured, and it was found that the compounds of the present invention had inhibitory effect on PDE4B2 enzyme, and the IC ₅₀ value was less than 1 μM; The IC ₅₀ value of the inhibitory effect on PDE4B2 enzyme is less than 500 nM; it is further found that the IC ₅₀ value of the inhibitory effect on the PDE4B2 enzyme of some example compounds of the present invention is less than 200 nM. Specifically, see Table 2 for the measurement results of the inhibitory effect of some example compounds of the present invention on PDE4B2 enzyme. [Table 2] Measurement results of the inhibitory effect of some compounds of the present invention on PDE4B2 enzyme Example number IC ₅₀ (nM) Example number IC ₅₀ (nM) Example 3 15.2 Example 78 2.3 Example 4 12.4 Example 79 40.67 Example 11 59.7 Example 80 59.57 Example 13 6.5 Example 81 1.00 Example 14 15.71 Example 82 1.68 Example 15 17.74 Example 83 5.78 Example 16 18.37 Example 84 43.5 Example 18 29.10 Example 85 10.44 Example 19 10.92 Example 86 0.73 Example 20 24.46 Example 87 4.58 Example 22 8.96 Example 89 9.86 Example 23 211.7 Example 90 5.00 Example 24 13.05 Example 91 1.48 Example 25 7.08 Example 92 9.15 Example 26 13.05 Example 93 1.68 Example 27 11.93 Example 94 34.42 Example 28 26.08 Example 95 16.32 Example 29 13.36 Example 96 5.89 Example 31 77.20 Example 98 5.62 Example 33 61.55 Example 99 22.7 Example 34 7.77 Example 100 0.42 Example 35 4.25 Example 101 1.87 Example 36 5.65 Example 102 0.94 Example 37 5.03 Example 103 12.54 Example 38 19.86 Example 106 0.2 Example 39 2.84 Example 107 0.48 Example 40 4.45 Example 108 26.97 Example 41 53.67 Example 109 124.9 Example 43 42.37 Example 110 1.66 Example 44 77.68 Example 111 1.71 Example 46 22.18 Example 114 47.48 Example 47 33.59 Example 115 69.37 Example 48 46.54 Example 117 19.69 Example 49 8.65 Example 120 49.84 Example 50 11.36 Example 121 34.09 Example 51 48.83 Example 122 9.86 Example 52 3.01 Example 123 13.2 Example 53 0.188 Example 124 0.33 Example 54 2.59 Example 125 4.91 Example 55 5.77 Example 126 17.89 Example 56 6.42 Example 127 14.66 Example 57 42.84 Example 128 5.93 Example 58 15.78 Example 129 15.08 Example 59 6.12 Example 130 23.07 Example 60 24.98 Example 131 0.42 Example 61 53.96 Example 132 0.45 Example 62 12.29 Example 133 0.49 Example 63 14.26 Example 134 10.72 Example 64 0.96 Example 135 16.74 Example 65 0.57 Example 136 3.11 Example 66 0.73 Example 137 11.11 Example 67 2.24 Example 138 45.96 Example 68 17.26 Example 139 51.27 Example 69 11.92 Example 140 35.29 Example 70 0.96 Example 141 55.57 Example 71 10.65 Example 142 29.36 Example 74 0.37 Example 143 10.0 Example 76 1.59 Example 144 79.86 Example 77 0.94 / / Example 148 29.08 Example 160 24.23 Example 151 12.79 Example 162 43.5 Example 152 0.99 Example 164 10.38 Example 153 3.43 Example 167 28.94 Example 154 5.87 Example 168 16.35 Example 155 2.91 Example 170 2.16 Example 156 4.71 Example 171 6.58 Example 158 66.91 Example 172 23.27 Example 159 40.74 / /

3. Experimental conclusion

Experiments show that the compounds of the present invention generally have a high inhibitory effect on PDE4B2 enzyme in vitro; especially the compounds in Table 2, they show significant inhibitory activity in the in vitro inhibition screening experiment on PDE4B2 enzyme.

Biological Example 2: PMA-induced acute atopic dermatitis mouse model by the compounds of the present invention

1. Test method

Select female ICR mice, weighing 26-28 g, and after 7 days of adaptive feeding, they were randomly divided into normal group, model group, and each compound group, with 4 mice in normal group and 10 mice in each other group. Except for the mice in the normal group, the other mice were smeared with 20 μL of PMA (Phorbol 12-myristate 13-acetate, phorbol ester) solution (dissolved in absolute ethanol) with a concentration of 0.25 mg/mL on the right ear model. The normal group Apply the corresponding solvent. Each compound group was given the first administration 30 minutes before modeling and the second administration 15 minutes after modeling. Animals in each group were smeared with 20 μL of the test drug solution with a concentration of 15 mg/mL [ethanol:acetone]. =1:1(v/v)], the animals in the normal group and model group were smeared with the corresponding vehicle. The animals were sacrificed 6 hours after the second administration, the right ear of each animal was cut off and the ear piece was obtained at a fixed position with an 8 mm ear punch and weighed. Homogenize in a homogenizer, take the supernatant after centrifugation, detect the concentrations of IL-1β and IL-6 in the supernatant, and calculate the protein concentration by the normalization method.

2. Experimental results

Tables 3 to 9 are the effects of the compounds of the present invention on the ear thickness, ear weight and secretion of inflammatory factors in the PMA-induced acute atopic dermatitis mice (Mean ± SEM, number of animals N = 4 or N = 10, similar to the model group. ratio, * indicates P < 0.05, ** indicates P < 0.01). [Table 3] Effects of compounds on mouse ear thickness and ear weight (Mean ± Sem) group Dosage N ear thickness ear weight Thickness(mm) Inhibition rate Weight (mg) Inhibition rate normal group - 4 0.222 ± 0.003** - 14.0 ± 0.5** - model group - 10 0.610 ± 0.019 - 38.6 ± 1.0 - Example 86 0.3 mg/ear/bid 10 0.310 ± 0.010** 77.3% 17.3 ± 0.7** 86.5% Example 25 0.3 mg/ear/bid 10 0.308 ± 0.012** 77.9% 20.6 ± 1.0** 73.4% Example 66 0.3 mg/ear/bid 10 0.270 ± 0.013** 88.5% 16.2 ± 1.0** 91.0% [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 0.276 ± 0.006** - 16.8 ± 0.7** - model group - 10 0.810 ± 0.017 - 44.8 ± 1.2 - Example 53 0.3 mg/ear/bid 10 0.548 ± 0.019** 49.2% 36.4 ± 1.5** 30.0% Example 106 0.3 mg/ear/bid 10 0.475 ± 0.030** 62.8% 27.7 ± 1.4** 61.1% Example 65 0.3 mg/ear/bid 10 0.565 ± 0.016** 45.8% 31.9 ± 0.9** 46.1% Continuation table group IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate normal group -0.174 ± 0.029** - 0.051 ± 0.005** - model group 3.215 ± 0.545 - 0.395 ± 0.037 - Example 53 0.506 ± 0.072** 79.9% 0.104 ± 0.006** 84.6% Example 106 0.623 ± 0.094** 76.5% 0.119 ± 0.018** 80.0% Example 65 0.420 ± 0.084** 82.5% 0.147 ± 0.026** 72.1% [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 0.255 ± 0.002** - 15.4 ± 1.4* - model group - 10 0.600 ± 0.032 - 29.7 ± 2.0 - Example 143 0.3 mg/ear/bid 10 0.362 ± 0.018** 68.9% 20.8 ± 1.5** 62.2% Example 133 0.3 mg/ear/bid 10 0.303 ± 0.023** 86.1% 20.2 ± 2.0** 66.4% Continuation table group IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate normal group -0.021 ± 0.006** - 0.095 ± 0.005** - model group 0.344 ± 0.043 - 0.358 ± 0.042 - Example 143 0.113 ± 0.018** 63.4% 0.243 ± 0.052 ( P ≈ 0.05) 43.6% Example 133 0.049 ± 0.013** 86.6% 0.039 ± 0.015** 85.2% [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 0.200 ± 0.000** - 12.4 ± 0.2** - model group - 10 0.395 ± 0.011 - 41.2 ± 1.2 - Example 39 0.3 mg/ear/bid 10 0.306 ± 0.008** 52.0% 23.1 ± 1.5** 62.8% Continuation table group IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate normal group -0.064 ± 0.004** - -0.025 ± 0.004** - model group 0.759 ± 0.217 - 0.398 ± 0.116 - Example 39 0.073 ± 0.012** 83.3% 0.025 ± 0.004** 88.3% [Table 7] Effects of compounds on mouse ear thickness, ear weight and inflammatory factors (Mean ± Sem) group Dosage N ear thickness ear weight Thickness(mm) Inhibition rate Weight (mg) Inhibition rate normal group - 4 0.202 ± 0.003** - 13.8 ± 0.4** - model group - 10 0.453 ± 0.009 - 36.5 ± 1.0 - Example 131 0.3 mg/ear/bid 10 0.249 ± 0.010** 81.1% 17.4 ± 0.5** 84.1% Example 132 0.3 mg/ear/bid 10 0.239 ± 0.009** 85.2% 17.4 ± 1.1** 84.1% Example 124 0.3 mg/ear/bid 10 0.298 ± 0.018** 61.7% 24.4 ± 1.8** 53.3% Continuation table group IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate normal group -0.034 ± 0.004** - -0.006 ± 0.005** - model group 0.163 ± 0.022 - 0.114 ± 0.016 - Example 131 0.062 ± 0.006** 51.4% 0.016 ± 0.004** 82.1% Example 132 0.018 ± 0.008** 73.4% 0.003 ± 0.004** 92.8% Example 124 0.049 ± 0.008** 57.8% 0.026 ± 0.007** 73.8% [Table 8] 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** - 12.80 ± 0.37** - model group - 10 0.483 ± 0.009 - 32.27 ± 0.85 - Example 138 0.3 mg/ear/bid 10 0.194 ± 0.031** 83.5% 16.50 ± 0.87** 81.0% Continuation table group IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate normal group -0.062 ± 0.005** - -0.047 ± 0.003** - model group 0.230 ± 0.026 - 0.182 ± 0.015 - Example 138 -0.014 ± 0.011** 83.5% -0.031 ± 0.007** 92.8% [Table 9] 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 0.195 ± 0.026** - 13.2 ± 0.3** - model group - 10 0.447 ± 0.019 - 36.7 ± 0.2 - Example 144 0.3 mg/ear/bid 10 0.266 ± 0.019** 72.0% 19.7 ± 0.2** 72.2% Continuation table group IL-1β IL-6 Concentration (pg/μg protein) Inhibition rate Concentration (pg/μg protein) Inhibition rate normal group -0.031 ± 0.025** - -0.027 ± 0.031** - model group 0.284 ± 0.034 - 0.102 ± 0.015 - Example 144 0.041 ± 0.016** 77.1% 0.006 ± 0.011** 74.8%

3. Experimental conclusion

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

Biological Example 3: OXA-induced chronic atopic dermatitis mouse model by the compounds of the present invention

1. Experimental method

Male Balb/c mice with a body weight of 24-26 g were selected. After 7 days of adaptive feeding, except for the normal group, the rest of the animals were coated with 40 μL of 1% OXA solution (dissolved in acetone) on the 0th and the first day. Mice were sensitized on both ears, and 40 μL of 0.5% OXA solution was applied to both ears of mice on the 7th and 8th days to repeat the sensitization, and the normal group was smeared with the corresponding vehicle. From the 12th day, except for the normal group, the other animals were challenged with 20 μl of 0.5% OXA solution applied to the right ear of the mice, twice a week, the normal group was applied with the corresponding vehicle, and the right ear was measured 24 hours after each challenge thickness. Except for the normal group, the other animals were randomly divided into the model group and each compound group on the 13th day according to the results of ear thickness, with 5 animals in the normal group and 10 animals in each other group. The administration started on the 14th day, twice a day, 20 μL of the test drug solution [ethanol:acetone=1:1 (v/v)] with a concentration of 15 mg/mL was applied to the ears of the animals in each administration group. Animals in the model group were smeared with the corresponding vehicle. On the 29th day, the ear thickness was measured and then sacrificed. The right ear of each animal was cut off and the ear piece was obtained at a fixed position with an 8 mm ear punch and weighed. Then, the ear piece was stored in liquid nitrogen, and then 500 μL of normal saline was added with a homogenizer. After homogenization, the supernatant was taken after centrifugation, and the concentrations of IL-1β, IL-4, IL-5, IL-6 and TNF-α in the supernatant were detected and the protein concentration was calculated by the normalization method.

2. Experimental results

It can be seen from the results that, compared with the model group, the compounds of the present invention can significantly reduce the ear thickness and end-point ear weight of OXA-induced chronic atopic dermatitis mice and the ear inflammatory factor IL-1β from the 20th day to the end of administration. , IL-4, IL-5, IL-6 and TNF-α secretion ( P < 0.01 ).

It will be apparent to those of ordinary skill in the art that this disclosure is not limited to the foregoing illustrative embodiments, but may be embodied in other specific forms without departing from essential characteristics thereof. Accordingly, it is intended that the various embodiments be regarded in all respects as illustrative and non-restrictive, and reference should be made to the appended claims, rather than to the foregoing embodiments, and, accordingly, to the meaning and scope of equivalents in the appended claims All changes within are included in the present invention.

In the description of this specification, reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., means a specific feature described in connection with the embodiment or example, A structure, material, or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention are described as examples, but are not limited to what is described in the present invention, and may also be modifications within the scope of the present invention or equivalents added in the claims. All publications or patents cited herein are incorporated herein by reference.

Claims (20)

A compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable compound represented by formula (I) Salts or their prodrugs:

(I); wherein: X is CH or N; Y is -(CH ₂ ) _m -C(=O)-NH-(CR ^m R ⁿ ) _p - or -(CH ₂ ) _m -C(=O) -O-(CR ^m R ⁿ ) _p -; A ring is a C _6-10 aryl group or a heteroaryl group consisting of 5-10 atoms; R ¹ is hydrogen, deuterium, -OR ^a or -NR ^c R ^d ; R ² is C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl, a hetero group consisting of 5-7 atoms cyclic group or (heterocyclic group consisting of 5-7 atoms)-C _1-4 alkyl; or R ² and R ^a and the atoms to which it is connected together form a heterocyclic group consisting of 5-7 atoms, the said Heterocyclyl consisting of 5-7 atoms is optionally selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , C _1-4 alkyl, C _1-4 alkoxy or halogenated C _1-4 alkyl substituent; R ³ is hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 alkyl-C(=O)-, HC(=O)-, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-S(=O) _2- Or C _1-6 alkyl-C(=NH)-, wherein said C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} alkyl-C(=O)-, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-S(=O) _2- and C _1-6 alkyl-C( = NH) - are each independently optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH ₂ to substituents; R ^4, R ^5a, R ^{5b, R 6, R 7a,} R 7b, R 8 and R ⁹ are each independently hydrogen, deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, -NO 2, -COOH, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, C _1-4 alkyl-C(=O)- or C _1-4 alkyl-S(=O) ₂ -; R ^a is hydrogen, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, heterocyclic group consisting of 5-10 atoms, C _6-10 aryl or 5-10 atoms composed of heteroaryl, wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, Heterocyclyl consisting of 5-10 atoms, C _6-10 aryl and heteroaryl consisting of 5-10 atoms are each independently optionally replaced by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or 5-1 substituted by the substituent of a heterocyclic group consisting of 0 atoms; each R ^{b is} independently deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl-OC(=O)-, C _1-6 alkyl-C(=O)-, C _1-6 alkyl- S(=O) ₂ -, C _3-8 cycloalkyl-C _1-6 alkyl, C _3-8 cycloalkyl, heterocyclic group composed of 5-10 atoms, C _6-10 aryl group, 5 -Heteroaryl composed of 10 atoms, -NR ^e C(=O)C _1-6 alkyl, -NR ^e R ^f , -S(=O) ₂ -NR ^e R ^f , -C(=O) -NR ^e R ^f or -C _1-6 alkyl-NR ^e R ^f , wherein said C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl-C _1-6 Alkyl, C _3-8 cycloalkyl, 5-10 atoms heterocyclic group, C _6-10 aryl group and 5-10 atom heteroaryl group are each independently optionally replaced by 1, 2, 3 or 4 selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, C _1-6 alkyl, C _1-6 alkylamino or C _1-6 substituted by the substituent of alkoxy; R ^c and R ^d are each independently hydrogen, -OH, C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl-C _{1- 4} alkyl, C _3-6 cycloalkyl, heterocyclyl composed of 5-7 atoms, (heterocyclyl composed of 5-7 atoms)-C _1-4 alkyl, C _1-4 alkyl- C (= O) - C _1-4 alkyl or _{-S (= O) 2 -;} R e and R ^{f are} each independently hydrogen, C _1-6 alkyl, C _1-6 alkyl -OC (= O)-, C _1-6 alkyl-C(=O)-, C _1-6 alkyl-S(=O) _2- , C _3-8 cycloalkyl, C _6-10 aryl, 5- Heterocyclic group consisting of 10 atoms, heteroaryl group consisting of 5-10 atoms, heteroaryl group consisting of 11-15 atoms, C _3-8 cycloalkyl-C _1-6 alkyl, C _6-10 Aryl-C _1-6 alkyl, (heterocyclyl consisting of 5-10 atoms)-C _1-6 alkyl, (heteroaryl consisting of 5-10 atoms)-C _1-6 alkyl or -C _1-6 alkyl-NR ^g R ^j ; or R ^e and R ^f together with the N atoms to which they are attached form a heterocyclic group consisting of 4-7 atoms; wherein said R ^e , R ^f and 4- The heterocyclic groups consisting of 7 atoms are each independently optionally substituted by 1, 2, 3 or 4 R ^h ; each R ^{h is} independently deuterium, F, Cl, Br, I, -OH, -CN, - NH _2, C _1-4 alkyl, C _{1-4 haloalkyl,} C _{1-4 haloalkoxy} or C _1-4 alkoxy; R ^g and R ^j are each independently hydrogen , C _1-4 alkyl, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-C(=O)-, C _1-4 alkyl-S(=O) _2- , C _3-6 cycloalkyl, C _6-10 aryl, heterocyclic group composed of 5-6 atoms or heteroaryl group composed of 5-6 atoms; R ^m and R ⁿ are each independently hydrogen, deuterium , F, Cl, Br, I, -OH, -CN, -NH ₂ , C _1-4 alkyl, halogenated C _1-4 alkyl, or -C(=O)NH ₂ ; each n is independently 0 , 1, 2, 3, or 4; m and p are each independently 0, 1, 2, or 3. The compound according to claim 1, wherein A ring is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, Thiazolyl, oxazolyl, indolyl, isoindolyl,

,

,

,

,

or

. The compound according to claim 1, wherein R ³ is hydrogen, deuterium, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _{1- 4} alkyl-C(=O)-, HC(=O)-, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-S(=O) ₂ - or C _{1- 4} alkyl-C(=NH)-, wherein, the C _1-4 alkyl group, C _1-4 alkoxy group, C _2-4 alkenyl group, C _2-4 alkynyl group, C _1-4 alkane group base-C(=O)-, _C1-4alkyl -OC(=O)-, _C1-4alkyl -S(=O) _2- and _C1-4alkyl -C(=NH) - each independently is optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN , or -NH ₂ to a substituent group. The compound of claim 1, wherein R ^a is hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 5-6 A heterocyclic group consisting of 1 atoms, a phenyl group or a heteroaryl group consisting of 5-6 atoms, wherein the C _1-4 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, C _{3 -6} cycloalkyl, 5-6 atom heterocyclyl, phenyl and 5-6 atom heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl or 5-6 Substituted by the substituent of the heterocyclic group consisting of atoms. The compound of claim 1, wherein each R ^{b is} independently deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, oxo, C _{1- 4} alkyl, C _1-4 alkoxy, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl-C(=O)-, C _1-4 alkyl-S(= O) _2- , C _3-6 cycloalkyl-C _1-4 alkyl, C _3-6 cycloalkyl, heterocyclyl composed of 5-6 atoms, phenyl, heterocyclic group composed of 5-6 atoms Aryl, -NR ^e C(=O)C _1-4 alkyl, -NR ^e R ^f , -S(=O) ₂ -NR ^e R ^f , -C(=O)-NR ^e R ^f or - C _1-4 alkyl-NR ^e R ^f , wherein the C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl-C _1-4 alkyl, C _{3- 6} -cycloalkyl, phenyl, 5-6 atoms heterocyclyl and 5-6 atoms heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 atoms selected from deuterium, F, Cl , Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, C _1-4 alkyl, C _1-4 alkylamino or C _1-4 alkoxy substituents. The compound of claim 1, wherein R ^e and R ^f are each independently hydrogen, C _1-4 alkyl, C _1-4 alkyl-OC(=O)-, C _1-4 alkyl- C(=O)-, C _1-4 alkyl-S(=O) ₂ -, C _3-6 cycloalkyl, C _6-10 aryl, heterocyclic group consisting of 5-7 atoms, 5- Heteroaryl composed of 7 atoms, heteroaryl composed of 14-15 atoms, C _3-6 cycloalkyl-C _1-4 alkyl, C _6-10 aryl-C _1-4 alkyl, ( Heterocyclyl consisting of 5-7 atoms)-C _1-4 alkyl, (heteroaryl consisting of 5-7 atoms)-C _1-4 alkyl or -C _1-4 alkyl-NR ^g R formed or R ^e and R ^f N atom to which they are attached form a 4-6 atom heterocyclic group consisting of;; ^J heterocyclyl wherein said R ^e, R ^f, and 4-6 atoms are each independently Optionally substituted with 1, 2, 3 or 4 ^Rh . The compound according to claim 1, wherein R ² is 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 , -CF ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ F, -CH ₂ CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -CF ₂ CH ₂ CH ₃ , - CH ₂ Cl, -CHCl ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, piperazinyl, piperidine group, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl or pyrrolidinylmethyl; or R ² and R ^a together with the atoms to which it is attached to form 1,3-dioxole, 1,3-dioxene, 2.3-dihydro-1,4,2-dioxazine or 1,5,3 - dioxazepine, said 1,3-dioxole, 1,3-dioxene, 2.3-dihydro-1,4,2-dioxazine or 1,5,3- dioxo-azepine, optionally substituted independently selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, -CHF ₂ , -CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CF ₃ or -CF ₂ CH ₃ substituent. The compound of claim 1, wherein R ³ is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy group, ethoxy, n-propoxy, isopropoxy, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, HC(=O)- , methyl-C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC(=O )-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-S(=O) ₂ -, ethyl-S (=O) ₂ -, n-propyl-S(=O) ₂ -, isopropyl-S(=O) ₂ -, methyl-C(=NH)-, ethyl-C(=NH)- , n-propyl-C(=NH)- or isopropyl-C(=NH)-; wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3- Propynyl, methyl-C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-OC (=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-S(=O) ₂ -, ethyl Base-S(=O) ₂ -, n-propyl-S(=O) ₂ -, isopropyl-S(=O) ₂ -, methyl-C(=NH)-, ethyl-C(= NH)-, n-propyl-C(=NH)- and isopropyl-C(=NH)- each independently optionally by 1, 2 or 3 selected from deuterium, F, Cl, Br, I, - Substituents of OH, -CN or -NH ₂ are substituted. The compound of claim 1, wherein R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , R ⁸ and R ⁹ are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, iso-propoxy, - _{CH 2 F, -CHF 2, -CF} 3, -CH 2 CH 2 F, -CH 2 CHF 2, -CH 2 CF 3, -CF 2 CH 3, -CH 2 CH 2 CH 2 F, -CH 2 CH ₂ CHF ₂ , -CH ₂ CH ₂ CF ₃ , -CF ₂ CH ₂ CH ₃ , -CH ₂ Cl, -CHCl ₂ , methyl-C(=O)-, ethyl-C(=O)-, n- Propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) ₂ -, n-propyl-S(= O) ₂ - or isopropyl-S(=O) ₂ -. The compound according to claim 1, wherein R ^a is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl , 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, Linyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazole group, imidazolyl, thiazolyl or oxazolyl; wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, 1-propenyl, 2-propenyl, ethynyl, 1-propynyl, 3-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholine base, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl , imidazolyl, thiazolyl and oxazolyl are independently optionally substituted with 1,2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, -NO 2, -COOH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Substituents of piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl or pyrrolidinyl. The compound of claim 1, wherein each R ^{b is} independently deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , -NO ₂ , -COOH, oxo, methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methyl-OC ( =O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(=O)-, ethyl- C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) ₂ - , n-propyl-S(=O) ₂ -, isopropyl-S(=O) ₂ -, cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl n-propyl, cyclopropyl isopropyl , cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetra Hydropyranyl, tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazole Base, -NR ^e C(=O) methyl, -NR ^e C(=O) ethyl, -NR ^e C(=O) n-propyl, -NR ^e C(=O) isopropyl, -NR ^e R ^f , -S(=O) ₂ -NR ^e R ^f , -C(=O)-NR ^e R ^f , -methyl-NR ^e R ^f , -ethyl-NR ^e R ^f , -n-propyl Base-NR ^e R ^f or -isopropyl-NR ^e R ^f ; wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropylmethyl, cyclopropylethyl, cyclopropyl-n-propyl, cyclopropylisopropyl, cyclobutylmethyl, Cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, Tetrahydrofuranyl, pyrrolidinyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl and oxazolyl are each independently optional substituted 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I , -OH, -CN, -NH 2, -NO 2, -COOH, methyl, ethyl, n-propyl, iso propyl, methylamino, dimethylamino, methoxy, ethoxy, n-propoxy or isopropoxy substituents. The compound of claim 1, wherein R ^c and R ^d are each independently hydrogen, -OH, 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, -CF 2 CH 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2, -CH 2 CH 2 CF ₃ , -CF ₂ CH ₂ CH ₃ , -CH ₂ Cl, -CHCl ₂ , cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, methyl-C (=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl base-S(=O) ₂ -, n-propyl-S(=O) ₂ - or isopropyl-S(=O) ₂ -. The compound of claim 1, wherein R ^e and R ^f are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl base, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl-C(= O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, methyl-S(=O) ₂ -, ethyl- S(=O) ₂ -, n-propyl-S(=O) ₂ -, isopropyl-S(=O) ₂ -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, Naphthyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl , thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, cyclopropylmethyl, cyclopropylethyl, cyclopropyl-n-propyl, cyclopropylisopropyl, cyclobutylmethyl , cyclopentylmethyl, cyclohexylmethyl, benzyl, phenethyl, heterocyclyl-C _1-4 alkyl consisting of 5-7 atoms, pyridylmethyl, pyrimidinylmethyl, furyl Methyl, thienylmethyl, pyrrolylmethyl, pyrazolylmethyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, -methyl-NR ^g R ^j , -ethyl-NR ^g R ^j , -n-propyl-NR ^g R ^j , -isopropyl-NR ^g R ^j or

; Or R ^e and R ^f together with the N atom they are connected to form an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group or a piperazinyl group; wherein, the R ^e , ^Rf , azetidine, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl are each independently optionally substituted with 1, 2, 3, or 4 ^Rh . The compound according to claim 1, wherein each R ^{h is} independently deuterium, F, Cl, Br, I, -OH, -CN, -NH ₂ , methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy , isobutoxy, sec-butoxy or tert-butoxy; R ^g and R ^j are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl, tert-butyl, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, methyl Base-C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, methyl-S(=O) ₂ -, ethyl-S(=O) ₂ -, n-propyl-S(=O) ₂ -, isopropyl-S(=O) ₂ -, isopropyl-C(=O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl Hexyl, phenyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl or oxazolyl; R ^m and R ⁿ are each independently hydrogen, deuterium, F, Cl, Br, I, -OH, -CN, -NH _2, 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, _{-CF 2 CH 3, -CH 2 Cl} , -CHCl 2 , or -C (= O) NH _2. The compound according to claim 1, which is a compound represented by formula (II) or (III), or a stereoisomer, tautomer, nitrogen oxide of a compound represented by formula (II) or (III) , hydrates, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs:

(II) or

(III). A compound which is a compound having one of the following structures or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or a compound having one of the following structures Their prodrugs:

(1),

(2),

(3),

(4),

(5),

(6),

(7),

(8),

(9),

(10),

(11),

(12),

(13),

(14),

(15),

(16),

(17),

(18),

(19),

(20),

(twenty one),

(twenty two),

(twenty three),

(twenty four),

(25),

(26),

(27),

(28),

(29),

(30),

(31),

(32),

(33),

(34),

(35),

(36),

(37),

(38),

(39),

(40),

(41),

(42),

(43),

(44),

(45),

(46),

(47),

(48),

(49),

(50),

(51),

(52),

(53),

(54),

(55),

(56),

(57),

(58),

(59),

(60),

(61),

(62),

(63),

(64),

(65),

(66),

(67),

(68),

(69),

(70),

(71),

(72),

(73),

(74),

(75),

(76),

(77),

(78),

(79),

(80),

(81),

(82),

(83),

(84),

(85),

(86),

(87),

(88),

(89),

(90),

(91),

(92),

(93),

(94),

(95),

(96),

(97),

(98),

(99),

(100),

(101),

(102),

(103),

(104),

(105),

(106),

(107),

(108),

(109),

(110),

(111),

(112),

(113),

(114),

(115),

(116),

(117),

(118),

(119),

(120),

(121),

(122),

(123),

(124),

(125),

(126),

(127),

(128),

(129),

(130),

(131),

(132),

(133),

(134),

(135),

(136),

(137),

(138),

(139),

(140),

(141),

(142),

(143),

(144),

(145),

(146),

(147),

(148),

(149),

(150),

(151),

(152),

(153),

(154),

(155),

(156),

(157),

(158),

(159),

(160),

(161),

(162),

(163),

(164),

(165),

(166),

(167),

(168),

(169),

(170),

(171),

(172),

(173),

(174),

(175),

(176),

(177),

(178),

(179),

(180),

(181),

(182),

(183),

(184),

(185),

(186),

(187),

(188),

(189),

(190),

(191),

(192),

(193),

(194),

(195),

(196),

(197),

(198),

(199),

(200),

(201),

(202),

(203),

(204),

(205),

(206),

(207),

(208),

(209),

(210),

(211),

(212),

(213),

(214),

(215),

(216),

(217),

(218),

(219),

(220),

(221),

(222),

(223),

(224),

(225),

(226),

(227),

(228),

(229),

(230),

(231),

(232),

(233),

(234),

(235),

(236),

(237),

(238),

(239),

(240),

(241) or

(242). A pharmaceutical composition comprising the compound of any one of claims 1 to 16, further comprising at least one of a pharmaceutically acceptable carrier, excipient, adjuvant, adjuvant or vehicle. The pharmaceutical composition of claim 17, further comprising an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, telukast, theophylline , formoterol, salmeterol, fluticasone propionate, rolipram, piramister, cilomilast, indacaterol, odaterol, midestane, qifluid, sardine alcoholamine, camoxirol, budesonide, beclomethasone dipropionate, flunisolide, roflunomide, ciclesonide, ipratropium bromide, oxytropium bromide, tiotropium bromide, Glycopyrronium bromide, umeclidinium bromide, vilanterol, aclidinium bromide, benralizumab, Tralokinumab, revatropate, cresabor, fluocinolone acetate, didometasone, mometasone, triamcinolone Dragon, betamethasone, aclomethasone, triamcinolone acetonide, desonide, hydrocortisone, clobetasol, halobetasol, mometasone furoate, diflurazone, meperocline, heparin Crolimus, Pimecrolimus, Tazarotene, Cyclosporine, Apremilast, E-6005, OPA-15406, LEO-29102, DRM02, Roflumilast, Ibudilast, Tofacitinib Nimolizumab, JTE-052, Baricitinib, Upatinib, WBI-1001, MRX-6, GSK2981278, Duluzumab, Lekinizumab, Nimolizumab, Traluzumab , etanercept, adalimumab, infliximab, ustecalumab, sekuginu, omazu, CIM-331, golimumab and pegylated race, tocilizumab , Calcipotriol, Calcitriol, Aliretinoin, VTP-38543, ZPL-389, Aprepitant, Tripitant, Faviprant, OC-459, SUN 13834, SB-011, VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02 or combinations thereof. A compound as claimed in any one of claims 1 to 16 or the use of the pharmaceutical composition as claimed in claim 17 or 18 in the preparation of a medicament, wherein the medicament is used for prevention, treatment or alleviation of the Phosphodiesterase-related diseases. The use according to claim 19, wherein the disease related to phosphodiesterase type 4 is respiratory disease, allergy, inflammation, central nervous system disease or non-insulin-dependent diabetes mellitus; Wherein, the respiratory diseases are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, pulmonary tuberculosis fibrosis, cystic fibrosis, acute respiratory distress syndrome Or inflammation of the respiratory tract; wherein bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis; Wherein, the inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatism Arthritis or psoriatic arthritis.