Substituted nitrogen five-membered ring derivatives and their application in medicine

Abstract

The present invention discloses substituted aza-five-membered ring derivatives and their use in medicine; specifically, the present invention provides a class of substituted aza-five-membered ring compounds or their stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutical compositions containing the compounds of the present invention. The present invention also discloses the use of the compounds of the present invention or their pharmaceutical compositions in the preparation of medicines, which are used to treat PDE4-related diseases, such as atopic dermatitis (AD) or chronic obstructive pulmonary disease (COPD).

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a class of substituted aza-five-membered ring derivatives, pharmaceutical compositions containing the derivatives, and uses and methods of use thereof. In particular, the compounds of the present invention are PDE4 inhibitors, which are used to treat PDE4-related diseases, such as atopic dermatitis (AD) or chronic obstructive pulmonary disease (COPD). Background Art

[0002] Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are two important second messengers in cells. They mainly participate in physiological activities such as energy metabolism, memory, immune response, vision and olfactory formation by activating protein kinase A (PKA) and protein kinase G (PKG) pathways. The regulation of their intracellular concentration is mainly determined by the balance between the synthesis of adenylate (guanylate) cyclase and the hydrolysis of phosphodiesterase (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, inhibiting PDEs is a very effective way to cause many cell activities, which can affect the activation of inflammatory cells and immune cells and the contraction response of smooth muscle cells.

[0003] Phosphodiesterases (PDEs) have been reported to have 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 hydrolyze cAMP, PDE5, PDE6 and PDE9 specifically hydrolyze cGMP, and PDE1, PDE2, PDE3, PDE10 and PDE11 act on both cAMP and cGMP. Among them, PDE4 is mainly distributed in various inflammatory cells, and its tissue distribution shows that it is closely related to the central nervous system and the immune system. Its inhibitors can be used to treat various diseases, including allergic and inflammatory diseases, diabetes, central nervous system diseases and pain.

[0004] At present, the research on PDE4 is mainly focused on immune and inflammatory diseases. Many well-known pharmaceutical companies in the world have taken PDE4 as a target for chronic inflammatory diseases. PDE4 inhibitors exert their anti-inflammatory effects mainly through the following pathways: (1) inhibiting the activity of multiple inflammatory mediators; (2) inhibiting the upregulation and expression of cell adhesion factors; (3) inhibiting the activation of blood leukocytes; (4) inducing cell apoptosis; (5) inducing the production of cytokines with inhibitory activity (such as interleukin-6); (6) inducing the release of catecholamines and endogenous hormones. The first generation of PDE4 inhibitors mainly include theophylline, rolipram and piclamilast. Rolipram has a certain therapeutic effect on neurological diseases such as Parkinson's disease, depression and anxiety. However, the first generation of PDE4 inhibitors are limited in clinical application due to serious side effects such as nausea and vomiting; the second generation of PDE4 inhibitors include Roflumilast and Cilomilast, among which Roflumilast is used to treat COPD and has certain therapeutic effects on other inflammatory diseases, such as ulcerative colitis and Crohn's disease. The third generation of PDE4 inhibitor Apremilast has been used to treat autoimmune diseases such as psoriasis, and has fewer side effects and is easier for patients to tolerate. WO / 2000 / 064260 discloses that the PDE4 inhibitor Ro 20-1724 1% cream is effective in treating psoriasis. WO 2000 / 009504 discloses another PDE4 inhibitor CP-80633 (0.5% ointment), which significantly improves the clinical score of atopic dermatitis (erythema, nodules and epidermal exfoliation). However, more PDE4 inhibitors that can effectively treat atopic dermatitis are still needed clinically. Summary of the invention

[0005] The present invention relates to novel substituted aza-five-membered ring derivatives and a method for treating atopic dermatitis. The compound of the present invention or a pharmaceutical composition containing the compound has a good therapeutic effect on atopic dermatitis as a PDE4 inhibitor.

[0006] In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I):

[0007]

[0008] in:

[0009] Ring A is

[0010] Each R1 and R 2 are independently hydrogen, deuterium, C 2-6 Alkyl, halogenated C 1-6 Alkyl, amino substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, heterocyclic group composed of 5-10 atoms, C 3-8 Cycloalkyl-C 1-6 Alkylene, heterocyclic group composed of 5-10 atoms -C 1-6 Alkylene, C 6-10 Aryl-C 1-6 Alkylene or heteroaryl-C 1-6 Alkylene;

[0011] R 3 For hydrogen, deuterium, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 5-10 atoms, heteroaryl group consisting of 5-10 atoms, C 3-8 Cycloalkyl-C 1-6 Alkylene, C 6-10 Aryl-C 1-6 Alkylene, heterocyclic group composed of 5-10 atoms -C 1-6 Alkylene, heteroaryl-C 1-6 Alkylene, C 1-6 Alkyl-C(=O)-, C 1-6 Alkoxy-C(=O)-, C 3-8 Cycloalkyl-C(=O)-, heterocyclic-C(=O)-, -C(=O)-NR a R b , C 1-6 Alkyl-S(=O) n -、C 3-8 Cycloalkyl-S(=O) n -、C 6-10 Aryl-S(=O) n -, heterocyclic group consisting of 5 to 10 atoms -S(=O) n - or heteroaryl-S(=O) consisting of 5 to 10 atoms n -, where R 3Optionally 1, 2 or 3 R 6 replaced by;

[0012] Each R 6 are independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkoxy-C(=O)-N(R c )-;

[0013] R 4 For hydrogen, deuterium, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)-OC 1-6 Alkyl, -C(=O)-NR a R b , -C 1-6 Alkylene-NR a R b , -C 1-6 Alkylene-N(R c )-C(=O)-C 1-6 Alkyl, -C 1-6 Alkylene-OP(=O)(R d )-NR a R b , C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 5-10 atoms, heteroaryl consisting of 5-10 atoms, heterocyclic group consisting of 5-10 atoms-C 1-6 Alkylene, heteroaryl-C 1-6 Alkylene, C 6-10 Aryl-C 1-6 Alkylene, C 6-10 Aryl-C(=O)-, heterocyclic-C(=O)- consisting of 5 to 10 atoms, or heteroaryl-C(=O)- consisting of 5 to 10 atoms, wherein R 4 Optionally 1, 2 or 3 R 7 replaced by;

[0014] Each R 7 are independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)-NR a R b , C 1-6Alkyl-C(=O)-N(R c )-、C 1-6 Alkoxy-C(=O)-N(R c )-、C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkoxy-C(=O)-, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 5-10 atoms or heteroaryl group consisting of 5-10 atoms;

[0015] Each R a and R b are independently hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 5-10 atoms, heteroaryl composed of 5-10 atoms, C 3-8 Cycloalkyl-C 1-6 Alkylene, C 6-10 Aryl-C 1-6 Alkylene, heterocyclic group composed of 5-10 atoms -C 1-6 Alkylene, heteroaryl-C 1-6 Alkylene, C 1-6 Alkyl-C(=O)- or -C 1-6 Alkylene-C(=O)-C 1-6 Alkoxy, where each R a and R b 1, 2 or 3 groups selected from fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, oxo (=O), C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 substituted with an alkoxy group;

[0016] Each R c are independently hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0017] R 5 are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0018] R d -OH, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl, C 6-10Aryl, heterocyclic group consisting of 5-7 atoms, heteroaryl group consisting of 5-7 atoms, C 6-10 Aryl-C 1-3 Alkylene- or -C 6-10 Aryl-C 1-3 alkyl;

[0019] n is 1 or 2.

[0020] Some of the embodiments are that each R 1 and R 2 are independently hydrogen, deuterium, C 2-3 Alkyl, halogenated C 1-3 Alkyl, amino substituted C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, heterocyclic group composed of 5-7 atoms, C 3-6 Cycloalkyl-C 1-3 Alkylene, heterocyclic group composed of 5-7 atoms -C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene or heteroaryl-C 1-3 alkyl.

[0021] Some of the embodiments are: 3 For hydrogen, deuterium, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 5-7 atoms, heteroaryl group consisting of 5-7 atoms, C 3-6 Cycloalkyl-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkyl, heterocyclic group composed of 5-7 atoms -C 1-4 Alkylene, heteroaryl-C 1-4 Alkylene, C 1-4 Alkyl-C(=O)-, C 1-4 Alkoxy-C(=O)-, C 3-6 Cycloalkyl-C(=O)-, heterocyclic-C(=O)-, -C(=O)-NR a R b , C 1-4 Alkyl-S(=O)n -、C 3-6 Cycloalkyl-S(=O) n -、C 6-10 Aryl-S(=O) n -, heterocyclic group consisting of 5 to 7 atoms -S(=O) n - or heteroaryl-S(=O) consisting of 5 to 7 atoms n -, where R 3 Optionally 1, 2 or 3 R 6 replaced by;

[0022] Among them, each R 6 are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 Alkoxy-C(=O)-N(R c )-;

[0023] Among them, the R a , R b , R c and n have the meanings as defined in the present invention.

[0024] Some of the embodiments are that each R c are independently hydrogen, deuterium, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0025] Some of the embodiments are: 4 For hydrogen, deuterium, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)-OC 1-6 Alkyl, -C(=O)-NR a R b , -C 1-6 Alkylene-NR a R b , -C 1-6 Alkylene-N(R c )-C(=O)-C 1-6 Alkyl, -C 1-4 Alkylene-OP(=O)(R d )-NR a R b , C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 5-10 atoms, heteroaryl consisting of 5-10 atoms, heterocyclic group consisting of 5-10 atoms-C 1-6Alkylene, heteroaryl-C 1-6 Alkylene, C 6-10 Aryl-C 1-6 Alkylene, C 6-10 Aryl-C(=O)-, heterocyclic-C(=O)- consisting of 5 to 10 atoms, or heteroaryl-C(=O)- consisting of 5 to 10 atoms, wherein R 4 Optionally 1, 2 or 3 R 7 substituted; wherein said R 7 Has the definition as described in the present invention.

[0026] Some of the embodiments are that each R 7 are independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)-NR a R b , C 1-6 Alkyl-C(=O)-N(R c )-、C 1-6 Alkoxy-C(=O)-N(R c )-、C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 1-6 Alkoxy-C(=O)-, C 3-8 Cycloalkyl, C 6-10 aryl, a heterocyclic group consisting of 5 to 10 atoms, or a heteroaryl group consisting of 5 to 10 atoms; wherein R a , R b and R c Has the definition as described in the present invention.

[0027] Some of the embodiments are that each R a and R b are independently hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 5-10 atoms, heteroaryl composed of 5-10 atoms, C 3-8 Cycloalkyl-C 1-6 Alkylene, C 6-10 Aryl-C 1-6 Alkylene, heterocyclic group composed of 5-10 atoms -C 1-6 Alkylene, heteroaryl-C 1-6 Alkylene, C 1-6Alkyl-C(=O)- or -C 1-6 Alkylene-C(=O)-C 1-6 Alkoxy, where each R a and R b 1, 2 or 3 groups selected from fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, oxo (=O), C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 1-4 substituted with an alkoxy group.

[0028] Some of the embodiments are: 5 is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, C 1-3 Alkyl or halogenated C 1-3 alkyl.

[0029] Some of the embodiments are that each R 1 and R 2 are independently hydrogen, deuterium, ethyl, n-propyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-CH 2 Cl, -CHCl 2 、-CH=CH 2 、-CH 2 CH=CH 2 、-C≡CH、-CH 2 C≡CH, aminomethyl, aminoethyl, amino-n-propyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, cyanomethyl, cyanoethyl, cyano-n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, cyclopropylethylidene, cyclobutylmethylene, cyclobutylethylidene, cyclopentylmethylene, cyclopentylethylidene, cyclohexylmethylene or cyclohexylethylidene.

[0030] Some of the embodiments are that the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II):

[0031]

[0032] The A ring is Where R 3 , R 4 and R 5 Has the meaning described in the present invention.

[0033] Some embodiments are wherein R 3 is hydrogen, deuterium, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH 2 F, -CHF 2 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 、-CH 2 Cl, -CHCl 2 、-CH 2 CH 2 Cl, -CH 2 CHCl 2 、-CH=CH 2 、-CH 2 CH=CH 2 、-C≡CH、-CH 2 C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, cyclopropyl-methylene, cyclopropyl-ethylidene, cyclobutyl-methylene, cyclobutyl-ethylidene, cyclopentyl-methylene, cyclopentyl-ethylidene, cyclohexyl-methylene, cyclohexyl-ethylidene, phenylmethylene, phenylethylidene, CH 3 -C(=O)-, CH 3 CH 2 -C(=O)-, CH 3 (CH 2 )2 -C(=O)-, CH 3 -OC(=O)-, CH 3 CH 2 -OC(=O)-, CH 3 (CH 2 ) 2 -OC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, heterocyclic-C(=O)- of 5 to 7 atoms, -C(=O)-NR a R b or phenyl-S(=O) n -, wherein the heterocyclic group consisting of 5 to 7 atoms is piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl or pyrrolidinyl, wherein R 3 Optionally 1, 2 or 3 R 6 replaced by;

[0034] Among them, the R a , R b and n have the meanings as defined in the present invention.

[0035] Some of the embodiments are that each R 6 are independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH 2 F, -CHF 2 , -CF 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 、-CH 2 Cl, -CHCl 2 、-CH 2 CH 2 Cl, -CH 2 CHCl 2 , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, CH 3 -OC(=O)-N(R c )-、CH 3 CH 2 -OC(=O)-N(R c )-、CH 3 (CH2 ) 2 -OC(=O)-N(R c )-or (CH 3 ) 2 CH-OC(=O)-N(R c )-.

[0036] Some of the embodiments are: 4 For hydrogen, deuterium, carboxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C(=O)-OC 1-4 Alkyl, -C(=O)-NR a R b , -C 1-4 Alkylene-NR a R b , -C 1-4 Alkylene-N(R c )-C(=O)-C 1-4 Alkyl, -C 1-4 Alkylene-OP(=O)(R d )-NR a R b , C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 5-7 atoms, heteroaryl consisting of 5-7 atoms, heterocyclic group consisting of 5-7 atoms-C 1-4 Alkylene, heteroaryl-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkylene, C 6-10 Aryl-C(=O)-, heterocyclic-C(=O)- consisting of 5 to 7 atoms, or heteroaryl-C(=O)- consisting of 5 to 10 atoms, wherein R 4 Optionally 1, 2 or 3 R 7 replaced by;

[0037] Among them, the R a , R b , R c , R d and R 7 Has the meaning described in the present invention.

[0038] Some of the embodiments are that each R 7 are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), carboxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, -C(=O)-NRa R b , C 1-3 Alkyl-C(=O)-N(R c )-、C 1-3 Alkoxy-C(=O)-N(R c )-、C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-C(=O)-O-, C 1-3 Alkoxy-C(=O)-, C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 5 to 7 atoms or heteroaryl group consisting of 5 to 7 atoms;

[0039] Among them, the R a , R b and R c Has the meaning described in the present invention.

[0040] Some of the embodiments are that each R a and R b are independently hydrogen, deuterium, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 5-7 atoms, heteroaryl composed of 5-10 atoms, C 3-6 Cycloalkyl-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkylene, heterocyclic group composed of 5-7 atoms -C 1-4 Alkylene, heteroaryl-C 1-4 Alkylene, C 1-4 Alkyl-C(=O)- or -C 1-4 Alkylene-C(=O)-C 1-4 Alkoxy, where each R a and R b 1, 2 or 3 groups selected from fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, oxo (=O), C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 1-4 substituted with an alkoxy group.

[0041] Some of the embodiments are: 4 is hydrogen, deuterium, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH 2 、-CH 2 CH=CH 2 、-C≡CH、-CH 2C≡CH, -C(=O)-O-CH 3 、-C(=O)-O-CH 2 CH 3 、-C(=O)-O-CH(CH 3 ) 2 、-C(=O)-NR a R b 、-CH 2 -NR a R b 、-CH 2 CH 2 -NR a R b 、-CH 2 CH 2 CH 2 -NR a R b 、-CH(CH 3 )-NR a R b , -C 1-3 Alkylene-N(R c )-C(=O)-C 1-3 Alkyl, -CH 2 -OP(=O)(R d )-NR a R b 、-CH 2 CH 2 -OP(=O)(R d )-NR a R b , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, 5-7 atoms composed of heterocyclic -C 1-4 Alkylene, heteroaryl-C 1-3 Alkylene, phenylmethylene, phenylethylene, a heterocyclic group consisting of 5-7 atoms -C(=O)-, a heteroaryl group consisting of 5-10 atoms -C(=O)-, wherein the heterocyclic group consisting of 5-7 atoms is piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl or pyrrolidinyl, and the heteroaryl group consisting of 5-10 atoms is pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, Where R 4 Optionally 1, 2 or 3 R 7 replaced by;

[0042] Among them, the R a , R b , R c , R d and R 7 Has the meaning described in the present invention.

[0043] Some of the embodiments are that each R 7 are independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH 2 F, -CHF 2 , -CF 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 、-CH 2 Cl, -CHCl 2 、-CH 2 CH 2 Cl, -CH 2 CHCl 2 , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -C(=O)-NR a R b , CH 3 -C(=O)-N(R c )-、CH 3 CH 2 -C(=O)-N(R c )-、CH 3 (CH 2 ) 2 -C(=O)-N(R c )-、CH(CH 3 ) 2 -C(=O)-N(R c )-、CH 3 -OC(=O)-N(R c )-、CH 3 CH 2 -OC(=O)-N(R c )-、CH(CH 3 ) 2 -OC(=O)-N(R c )-、CH 3 -C(=O)-, CH3 CH 2 -C(=O)-, CH(CH 3 ) 2 -C(=O)-,,CH 3 -C(=O)-O-, CH 3 CH 2 -C(=O)-O-, CH(CH 3 ) 2 -C(=O)-O-, CH 3 -OC(=O)-, CH 3 CH 2 -OC(=O)-, CH 3 (CH 2 ) 2 -OC(=O)-, CH(CH 3 ) 2 -OC(=O)-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl or azetidinyl;

[0044] Among them, the R a , R b and R c Has the meaning as described in the present invention.

[0045] Some of the embodiments are that each R a and R b are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH 2 F, -CHF 2 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 、-CH 2 Cl, -CHCl 2 、-CH 2 CH 2 Cl, -CH 2 CHCl 2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl, cyclopropyl-methylene, cyclopropyl-ethylidene, cyclobutyl-methylene, cyclobutyl-ethylidene, cyclopentyl-methylene, cyclopentyl-ethylidene, cyclohexyl-methylene, cyclohexyl-ethylidene, phenylmethylene, phenylethylidene, CH 3 -C(=O)-, CH 3 CH 2 -C(=O)-, CH(CH 3 ) 2 -C(=O)-, -C 1-3 Alkylene-C(=O)-C 1-3 Alkoxy, and

[0046] Among them, each R a and R b is independently optionally substituted by 1, 2 or 3 groups selected from fluorine, chlorine, bromine, iodine, hydroxy, amino, cyano, oxo (=O), methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH 2 F, -CHF 2 , -CF 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 、-CH 2 Cl, -CHCl 2 、-CH 2 CH 2 Cl or -CH 2 CHCl 2 substituted by a group.

[0047] Some of the embodiments are: d It is -OH, methyl, ethyl, phenyl and pyridyl.

[0048] Some of the embodiments are that the present invention includes but is in no way limited to compounds having one of the following structures or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of compounds having one of the following structures:

[0049]

[0050]

[0051] In some embodiments, the compound represented by formula (I) or the compound represented by formula (II) 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, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate or a combination thereof.

[0052] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or formula (II) disclosed in the present invention.

[0053] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, additive, adjuvant, vehicle or any combination thereof.

[0054] In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, talukast, theophylline, formoterol, salmeterol, fluticasone propionate, rolipram, pyramister, cilomilast, indacaterol, olodaterol, mildestane, zilopentam, salbutamol, carmoxicillin, budesonide, beclomethasone dipropionate , triamcinolone acetonide, flunisolide, mometasone furoate, roflenide, ciclesonide, ipratropium, oxitropium, tiotropium, glycopyrrolate, umeclidinium, vilanterol, aclidinium, benralizumab, tralokinumab, revatolide, crisabor, fluocinolone acetate, desoximetasone, mometasone, triamcinolone, betamethasone, alclometasone, desonide, hydrocortisone, clobeta Clobatsol, halobetasol, diflorasone, meproclone, tacrolimus, pimecrolimus, tazarotene, cyclosporine, apremilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, ibudilast, tofacitinib, JTE-052, baricitinib, upadacitinib, WBI-1001, MRX-6, GSK2981278, Durulumab, levitra, nimolizumab, troloxinumab, etanercept, adalimumab, infliximab, ustekinumab, secukinumab, omalizumab, CIM-331, golimumab and peg-pegylated thiabendazole, tocilizumab, calcipotriol, calcitriol, alitretinoin, VTP-38543, ZPL-389, aprepitant, tredipitant, fulvepiprant, 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.

[0055] On the other hand, the present invention relates to the use of the compound represented by formula (I) or formula (II) disclosed in the present invention or its pharmaceutical composition in the preparation of a drug, wherein the drug is used to prevent, treat or alleviate diseases related to type 4 phosphodiesterase (PDE4).

[0056] In some embodiments, the disease associated with type 4 phosphodiesterase is a respiratory disease, allergy, inflammation, a central nervous system disease, pulmonary fibrosis or non-insulin dependent diabetes mellitus.

[0057] In some other embodiments, the respiratory disease is: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; wherein bronchitis includes acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;

[0058] The inflammation described herein is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis.

[0059] Another aspect of the present invention relates to a method for preparing, separating and purifying the compound represented by formula (I) or formula (II).

[0060] The foregoing description only summarizes certain aspects of the present invention, but is not limited to these aspects. These aspects and other aspects will be described in more detail and fully below.

[0061] Detailed description of the invention

[0062] Definitions and general terms

[0063] Certain embodiments of the present invention are now described in detail, and examples thereof are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is by no means limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0064] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0065] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0066] Unless otherwise indicated, the following definitions used in the present invention shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0067] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0068] The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human. The term "patient" as used in the present invention refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

[0069] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0070] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0071] The term "chiral" refers to a molecule that has the property of being non-superimposable on its mirror image; whereas "achiral" refers to a molecule that is superimposable on its mirror image.

[0072] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0073] The term "diastereoisomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0074] The stereochemical definitions and conventions 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.

[0075] Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane polarized light caused by a compound, wherein (-) or l indicates that the compound is levorotatory and the compound prefixed with (+) or d is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0076] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0077] Depending on the choice of starting materials and process, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0078] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0079] Any racemate of the resulting final product or intermediate can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereomeric salts obtained. The racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed.Robert E.Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of NotreDame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0080] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0081] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the above general formula compounds, or as the specific examples, subclasses, and classes of compounds included in the embodiments.

[0082] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted by one or more substituents selected from a specified group, the substituents may be the same or different at each position.

[0083] The term "optionally substituted with..." means that the structure is unsubstituted or substituted with one or more substituents described herein. Substituents described herein include, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, amino, carboxyl, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, haloalkyl, haloalkoxy, hydroxy substituted alkyl, hydroxy substituted alkoxy, amino substituted alkyl, cyano substituted alkyl, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-OC(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) 2 -, carboxyalkoxy, NH 2 -C(=O)-,NH2 -S(=O) 2 -, aryl-alkylene, heteroaryl-alkylene, heterocyclyl-alkylene, cycloalkyl-alkylene, and the like.

[0084] In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used in the present invention such as "each ... independently is" and "... independently is" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or in the same group, the specific options expressed by the same symbols do not affect each other. For example, the structural formula "-C(=O)-NR a R b " and structural formula "-C 1-6 Alkylene-NR a R b "Between the two a The specific options do not affect each other.

[0085] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1 -C 6 Alkyl" or "C 1-6 "Alkyl" refers specifically to methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 alkyl.

[0086] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is connected.

[0087] The term "alkyl" or "alkyl group" as used herein refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein, wherein the substituents are deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, amino, carboxyl, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, haloalkyl, haloalkoxy, hydroxy-substituted alkyl, hydroxy-substituted alkoxy, amino-substituted alkyl, cyano-substituted alkyl, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-OC(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) 2 -, carboxyalkoxy, NH 2 -C(=O)-,NH 2 -S(=O) 2 -, aryl-alkylene, heteroaryl-alkylene, heterocyclyl-alkylene, cycloalkyl-alkylene, and the like. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In one embodiment, an alkyl group contains 1-12 carbon atoms; in another embodiment, an alkyl group contains 1-6 carbon atoms; in yet another embodiment, an alkyl group contains 1-4 carbon atoms; in yet another embodiment, an alkyl group contains 1-3 carbon atoms.

[0088] 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 (-CH2 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.

[0089] The term "alkylene" means a saturated divalent hydrocarbon radical derived from a saturated straight or branched hydrocarbon by removing two hydrogen atoms. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In one embodiment, an alkylene group contains 1-6 carbon atoms; in another embodiment, an alkylene group contains 1-4 carbon atoms; in yet another embodiment, an alkylene group contains 1-3 carbon atoms; in yet another embodiment, an alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -)etc.

[0090] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms and having at least one site of unsaturation, i.e., a carbon-carbon sp 2 double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including "cis" and "tans" orientations, or "E" and "Z" orientations. 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 )etc.

[0091] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In 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.

[0092] The term "carboxyl", whether used alone or in combination with other terms, such as "carboxyalkyl", refers to -CO 2 H or -COOH.

[0093] The term "deuterium" refers to a single deuterium atom. For example, a deuterium atom replaces one hydrogen atom in a methyl group to form a mono-deuterated methyl group (-CDH 2 ), two deuterium atoms replace the two hydrogen atoms in the methyl group to form a di-deuterated methyl group (-CD 2 H), and three deuterium atoms replace the three hydrogen atoms in the methyl group to form a tri-deuterated methyl group (-CD 3 ).

[0094] As used herein, the term "unsaturated" means that the group contains one or more degrees of unsaturation.

[0095] 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 in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl).

[0096] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0097] The term "hydroxy substituted alkyl" means an alkyl group substituted by one or more hydroxy groups, wherein the alkyl group has the meaning as described herein. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like.

[0098] The term "cyano-substituted alkyl" means an alkyl group substituted by one or more cyano groups, wherein the alkyl group has the meaning as described herein. Such examples include, but are not limited to, cyanomethyl, cyanoethyl, and the like.

[0099] The term "amino-substituted alkyl" or "aminoalkyl" includes C substituted with one or more amino groups. 1-10 In some embodiments, aminoalkyl is a C substituted with one or more amino groups. 1-6 "Lower aminoalkyl", wherein the alkyl group has the meaning as defined herein. Examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

[0100] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In 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 contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein.

[0101] 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-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy(s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy(t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy(-OCH(CH3 )CH 2 CH 2 CH 3 ), 3-pentyloxy(-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy(-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy(-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ),etc.

[0102] The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, 1-chloroethyl, 1,1-dichloroethyl, difluoromethoxy, trifluoromethoxy, and the like.

[0103] The term "jk atoms", wherein each j and k are independently any non-zero natural numbers, and k>j; the "jk" includes j, k and any natural number between the two. Typically describes the number of ring atoms in a molecule, in which the number of ring atoms in the molecule is jk, and the atoms include carbon atoms and / or heteroatoms such as O, N, S, and P.

[0104] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In one embodiment, the cycloalkyl contains 3 to 12 carbon atoms; in another embodiment, the cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl contains 3 to 6 carbon atoms. The cycloalkyl group may be independently optionally substituted with one or more substituents described herein.

[0105] The terms "cycloalkylalkyl" or "cycloalkyl-alkylene" are used interchangeably and refer to an alkyl group substituted by one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group have the meanings as described herein, such examples include, but are not limited to, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene, cyclopentyl-ethylene, cyclohexyl-methylene, cyclohexyl-ethylene, and the like.

[0106] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, wherein the monocyclic, bicyclic or tricyclic ring does not contain an aromatic ring and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group may be a carbon group or a nitrogen group, and -CH 2 -groups may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to an S-oxide. The nitrogen atom of the ring may be optionally oxidized to an N-oxide. Examples of heterocyclic groups include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl. -CH in the heterocyclic group 2 Examples of -groups substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, and 3,5-dioxopiperidinyl. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. The heterocyclic group may be optionally substituted with one or more substituents described herein.

[0107] The term "heterocyclylalkyl" or "heterocyclyl-alkylene" may be used interchangeably and refer to an alkyl group substituted with a heterocyclyl group; wherein the heterocyclyl and alkyl groups have the meanings as described herein. Such examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetane-3-ylmethyl, pyrrolidin-2-ylmethyl, morpholin-4-ylmethyl, and the like.

[0108] The term "aryl" refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains a ring consisting of 3-7 atoms and has one or more attachment points to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include phenyl, naphthyl and anthracenyl. The aryl groups can be independently optionally substituted with one or more substituents described herein.

[0109] The term "arylalkyl" or "arylalkylene" can be used interchangeably and refers to an alkyl group substituted with one or more aryl groups, wherein the aryl and alkyl groups have the meanings described herein. In some embodiments, the arylalkyl group refers to a "lower arylalkyl" group, i.e., an aryl group attached to a C 1-6 In some other embodiments, the arylalkyl group refers to a C-containing 1-4 "Phenylalkyl" of alkyl. Specific examples thereof include diphenylmethyl, phenylmethylene, and phenylethylene. The aryl group on the arylalkyl or arylalkylene group may be further substituted with the substituents described in the present invention.

[0110] The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-7 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, the 5-10 heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, S, N or B.

[0111] Examples of heteroaryl groups include, but are not limited to, furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (such as 3-pyridazinyl), thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), thienyl (such as 2-thienyl, 3-thienyl), pyrazolyl (such as 2-pyrazolyl), isothiazolyl, pyrimidinyl, pyridinyl; also include the following bicyclic rings, but are by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), etc.

[0112] The terms "heteroarylalkyl" or "heteroarylalkylene" are used interchangeably and refer to an alkyl group substituted with one or more heteroaryl groups, wherein the heteroaryl and alkyl groups have the meanings described herein, such examples include, but are not limited to, imidazol-2-ylmethylene, furan-2-ylethylene, indol-3-ylmethylene, and the like.

[0113] As described in the present invention, a substituent is connected to the central ring by a bond to form a ring system (as shown in formula c), which means that the substituent can be substituted at any substitutable position on the ring. For example, formula c means that the substituent R can be substituted mono- or poly-substituted at any possible substitutable position on the C ring, as shown in formula c1 to formula c19.

[0114]

[0115] As described in the present invention, a linker is connected to the ring system (as shown in formula d), which means that the linker can be connected to the rest of the molecule at any possible position on the ring system. Formula d means that any possible position on the ring can be connected to the rest of the molecule, as shown in formulas d1 to d5.

[0116]

[0117] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) or (II) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0118] "Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by administering a compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of a compound, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0119] The "pharmaceutically acceptable salt" used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a group of N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0120] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0121] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. A special example of an N-oxide is an N-oxide of a tertiary amine or an N-oxide of a nitrogen-containing heterocyclic nitrogen atom. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA).

[0122] The term "carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, which are known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except for the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical composition is covered.

[0123] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing 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 physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0124] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic part by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., 1985; and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) can be found in a list of other suitable salts.

[0125] In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of containing their solvents (such as ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in the present invention can form solvates with pharmaceutically acceptable solvents (including water) inherently or by design; therefore, the present invention is intended to include both solvated and unsolvated forms.

[0126] Any structural formula given herein is also intended to represent non-isotopically enriched forms of these compounds as well as isotopically enriched forms. Isotopically enriched compounds have structures depicted by the general formula given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 Oh, 18 Oh, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0127] In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example, wherein a radioactive isotope is present, such as 3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 C. This type of isotope-enriched compound can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiation therapy of the patient. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) or (II) can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotopically labeled reagents to replace the unlabeled reagents used originally as described in the examples and preparation processes of the present invention.

[0128] In addition, heavier isotopes, especially deuterium (i.e. 2 H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, increased half-life in vivo 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 shown in formula (I) or formula (II). The concentration of such heavier isotopes, especially deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the solvent of crystallization may be isotopically substituted, such as D 2 O, acetone-d 6 DMSO-d 6 Those solvates.

[0129] Pharmaceutical compositions, preparations and administration of the compounds of the present invention

[0130] The present invention provides a pharmaceutical composition, comprising a compound represented by formula (I) or (II) or a single stereoisomer thereof, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient or adsorbent, and optionally, other therapeutic and / or preventive ingredients.

[0131] Suitable carriers, excipients or adsorbents are well known to those skilled in the art and are described in detail, for example, in 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.

[0132] As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or solvent that is relevant to the consistency of the dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would significantly reduce the efficacy of the disclosed compounds when administered to a patient and interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable. In addition, each excipient must be pharmaceutically acceptable, for example, having a sufficiently high purity.

[0133] Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected. In addition, pharmaceutically acceptable excipients may be selected based on their specific functions in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can help produce a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected that can help produce a stable dosage form. Certain pharmaceutically acceptable excipients may be selected that help carry or transport the compounds of the invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected to enhance patient compliance.

[0134] Some suitable examples of excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose. Suitable pharmaceutically acceptable excipients also include the following types of excipients: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adherents, antioxidants, chelating agents, penetration enhancers, pH adjusters, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents and filter aids. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function and may provide alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation. The compounds of the invention may be formulated using methods known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to a patient.

[0135] The skilled person has the knowledge and skill in the art to enable them to select a suitable pharmaceutically acceptable excipient for the appropriate amount of the present invention. In addition, there are a large number of resources available to the skilled person that describe pharmaceutically acceptable excipients and are used to select 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).

[0136] 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 York, various carriers for configuring pharmaceutically acceptable compositions, and known techniques for their preparation are disclosed, and the respective contents of these documents are incorporated by reference into the present invention. Except any conventional carriers such as any undesirable biological effects are produced, or any other components in the pharmaceutically acceptable compositions are interacted in a harmful manner and are incompatible with the compounds of the present invention, it is concerned that their application belongs to the scope of the present invention.

[0137] Suitable pharmaceutically acceptable carriers depend on the pharmaceutical form and are known to those skilled in the art.

[0138] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents and solvent mixtures, coatings, complexing agents, solid carriers, dispersion media, surface active excipients, antibacterial and antifungal agents, isotonic and absorption delaying agents for pharmaceutically active substances, and mixtures thereof, which are also known in the art.

[0139] Non-limiting examples of pharmaceutically acceptable carriers include those having components selected from the group consisting of lactose, gelatin, sugar alcohols (e.g., starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, colloidal silicon dioxide, carboxymethyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, buffered aqueous solution, copovidone, polysorbate, ethanol, propylene glycol, polyethylene glycol (preferably polyethylene glycol, e.g., PEG400), 80 (i.e. PEG (20), sorbitan monooleate), DMSO, a mixture of water and a cosolvent, for example, an aqueous solution comprising an alcohol such as ethanol and / or a polyglycol such as polyethylene glycol, an ester of a polyol such as glycerol and / or polyethylene glycol with a fatty acid, a surfactant such as an anionic, cationic, nonionic and amphoteric surfactant, a complexing agent such as a cyclodextrin, for example α-cyclodextrin (α-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD), a salt of a bile acid or a lipid such as an animal or plant phospholipid, a micellizing agent, and an oil such as corn oil, or a mixture of two or more of the aforementioned components.

[0140] Further non-limiting examples of suitable pharmaceutically acceptable carriers and suitable additives that can be used in the pharmaceutical compositions of the present invention are mentioned below.

[0141] In one embodiment, the present invention relates to a pharmaceutical composition of the present invention, which forms a lipid-based drug delivery system (DDS) in an aqueous medium. The pharmaceutical composition, in addition to at least one compound or its salt in the compound shown in formula (I) or (II), also includes at least one surfactant. Non-limiting examples of suitable surfactants are as described above. In various embodiments, the lipid-based drug delivery system forms the following structures: (1) liposomes (i.e., dispersed closed bilayer assemblies of lamellar phases in water); (2) nanoparticles of non-lamellar phases (e.g., cubes, hexagons, sponges); or (3) micelles, emulsions, microemulsions (i.e., simple self-assembled structures of lipids and surfactants).

[0142] In some embodiments, the drug delivery system based on lipid that forms micelle, emulsion or microemulsion is preferred.The hydrophilic-lipophilic balance value (HLB-value) of suitable surfactant or surfactant mixture for forming micelle, emulsion or microemulsion is generally about 8-18, about 10-18, or about 12-16.Drug delivery system based on lipid forms self-emulsifying drug delivery system (SEDDS) or self-microemulsifying drug delivery system (SMEDDS).SEDDS and SMEDDS are oil (i.e. lipid, compound of formula (I) or its salt), at least one surfactant, optionally at least one cosolvent and optionally at least one cosurfactant mixture, ideally isotropic, when introduced into water phase under gentle stirring, it spontaneously emulsifies and forms oil-in-water emulsifier.Gentle stirring can be provided for example by the activity of stomach.

[0143] The pharmaceutical compositions disclosed in the present invention are prepared using techniques and methods known to those skilled in the art. Some common methods described in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0144] Therefore, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof, the process comprising mixing the various ingredients. The pharmaceutical composition comprising a compound disclosed herein can be prepared by mixing at, for example, ambient temperature and atmospheric pressure.

[0145] The compounds disclosed herein are generally formulated into dosage forms suitable for administration to a patient via a desired route. For example, the dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0146] Various solid oral dosage forms are used for administration of the compounds of the present invention, such as solid dosage forms of tablets, capsules, granules, lozenges, and bulk powders.

[0147] The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers and excipients known in the art (e.g., sucrose, mannitol, lactose, starch), including but not limited to suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavoring agents, lubricants, etc. Timed-release capsules, tablets, and gels are also advantageous for the administration of the compounds of the present invention.

[0148] Various external dosage forms can be used for the administration of the compounds of the present invention, such as lotions, ointments, tinctures, liniments, spirits, powders, creams, oils, pastes, plasters, film coatings and aerosols. Topical administration can also include transdermal administration by means of, for example, transdermal patches. The compounds of the present invention can be administered alone or in combination with various pharmaceutically acceptable carriers, diluents and excipients known in the art, including but not limited to solvents, oily solvents, diluents, tranquilizers, absorption delay agents, disintegrating agents, emulsifiers, antioxidants, adhesives, bonding agents, tackifiers, solubilizing agents, dispersants, suspoemulsifiers, lubricants, hygroscopic agents, liposomes, microemulsions and beta-cyclodextrins, etc.

[0149] For the treatment of respiratory diseases, preferably the compounds of the invention are administered by inhalation.

[0150] Inhalable preparations include inhalable powders, metered aerosols containing propellants or inhalable preparations without propellants. For this purpose, the powders (preferably micronized forms) can be administered directly, or by spray solutions or suspensions containing them.

[0151] To the powdered compound of the invention may be added an excipient or carrier which is generally non-toxic and chemically inert toward the compound of the invention, such as lactose or any other additive suitable for improving the respirable fraction.

[0152] Inhalation aerosols containing gaseous propellants such as hydrofluoroalkanes may contain the compounds of the invention in solution or dispersed form. Propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.

[0153] Propellant-free inhalable formulations containing the compounds of the invention may be in the form of solutions or suspensions in aqueous, alcoholic or hydroalcoholic media, and they may be delivered by jet nebulizers or ultrasonic nebulizers known in the art, or by soft-mist nebulizers such as deliver.

[0154] The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show a beneficial therapeutic effect. For example, an amount sufficient to treat, cure or alleviate the symptoms of a disease when administered or brought into balance in the body. The effective amount required for a particular treatment regimen depends on a variety of factors, including the disease being treated, the severity of the disease, the activity of the specific drug used, the method of administration, the clearance rate of the specific drug, the duration of treatment, combined medication, age, weight, sex, diet and health of the patient, etc. A description of other factors that need to be considered in the art regarding the "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.

[0155] The dosage of the compounds of the invention depends 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, toxicological profile, and pharmacokinetic characteristics of the compound.

[0156] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. For example, a formulation intended for application to a human being may conveniently contain from about 5 mg to about 250 mg / kg body weight / day of active agent, compounded with a suitable and convenient amount of carrier material (which may account for about 5% to about 95% of the total composition). A unit dosage form will generally contain from about 1 mg to about 500 mg of active ingredient.

[0157] Advantageously, they are administered in a dosage of 5-250 mg / kg body weight / day, preferably 25-150 mg / kg body weight / day.

[0158] The term "administration" refers to providing a therapeutically effective amount of a drug to an individual, and the administration methods include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, etc. The dosage forms include ointments, lotions, tablets, capsules, pills, flying powders, granules, suppositories, pills, lozenges, injections, sterile solutions or non-aqueous solutions, suspensions, emulsions, patches, etc. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (such as glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

[0159] The preferred route of administration will vary with clinical characteristics, and the change in dosage must depend on the condition of the patient being treated. The doctor will determine the appropriate dosage based on the individual patient. The therapeutically effective amount per unit dose depends on body weight, physiological function and the selected vaccination regimen. The compound per unit dose refers to the weight of the compound at each administration, excluding the weight of the carrier (the drug contains a carrier).

[0160] Any suitable route of administration can be used to provide an effective dose of the compound of the present invention to a mammal, especially a human. For example, oral administration, rectal administration, parenteral administration, topical administration, ocular administration, nasal administration, pulmonary administration, etc. can be adopted. Dosage forms include tablets, lozenges, capsules, creams, ointments, suspensions, dispersions, solutions, aerosols, etc. Preferably, the compound shown in formula (I) or (II) is administered by inhalation or topical administration.

[0161] The pharmaceutical composition provided by the present invention can be formulated into single dose or multiple dose administration. The single dose preparation is packaged in an ampoule, a vial or a syringe. The multiple dose parenteral preparation must contain an antimicrobial agent at a bacteriostatic or antifungal concentration. All parenteral preparations must be sterile, as known and practiced in the art.

[0162] The pharmaceutical composition provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or co-formulated with substances that supplement the intended effect.

[0163] In one embodiment, the treatment method of the present invention comprises administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need thereof. Various embodiments of the present invention include treating the diseases mentioned in the present invention by administering a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention to a patient in need thereof.

[0164] In one embodiment, the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention can be administered once, or several times at different time intervals within a specified time period according to a dosing regimen. For example, once, twice, three times or four times a day. In one embodiment, it is administered once a day. In another embodiment, it is administered twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosing regimen of the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by a technician. In addition, the appropriate dosing regimen of the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, including the duration of the implementation of the regimen, depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, etc., within the knowledge and experience of the technician. Such a technician should also understand that for individual patients' responses to the dosing regimen, or when individual patients' needs change over time, it may be required to adjust the appropriate dosing regimen.

[0165] The compounds of the present invention can be administered simultaneously with one or more other therapeutic agents, or before or after them. The compounds of the present invention can be administered separately with other therapeutic agents by the same or different routes of administration, or in the form of the same pharmaceutical composition. This is selected by those skilled in the art based on the actual physical conditions of the patient, such as health, age, weight, etc. If formulated as a fixed dose, this combination product uses the compounds of the present invention (within the dosage range described in the present invention) and other pharmaceutically active agents (within its dosage range).

[0166] Accordingly, in one aspect, the present invention includes a combination comprising a quantity 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 additional therapeutic agents as described above.

[0167] The compound shown in formula (I) or (II) can be used in combination with other drugs for preventing, treating or alleviating the disease or symptom to which the compound shown in formula (I) or (II) is applicable. These other drugs can be administered simultaneously or successively with the compound shown in formula (I) or (II) through their commonly used routes and amounts. When the compound shown in formula (I) or (II) is used simultaneously with one or more other drugs, a pharmaceutical unit dosage form containing such other drugs and the compound shown in formula (I) or (II) is preferred.

[0168] In various embodiments, the compounds described herein are combined with other drugs to provide a combination therapy for chronic obstructive pulmonary disease (COPD), atopic dermatitis (AD), psoriasis or other conditions. The pharmaceutical compositions of the present invention include at least one of the PDE4 inhibitors described herein and an additional therapeutic agent, examples of which include, but are not limited to:

[0169] (1) β2-agonists, such as albuterolamine, formoterol, salmeterol, and carmoxicillin;

[0170] (2) corticosteroids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, flunisolide, mometasone furoate, roflenone, ciclesonide, fluocinolone acetonide, desoximetasone, mometasone, triamcinolone, betamethasone, alclomethasone, desonide, hydrocortisone, meproclofen;

[0171] (3) anticholinergics or antimuscarinics, such as ipratropium, oxitropium, tiotropium, glycopyrrolate, and revatropate;

[0172] (4) topical calcineurin inhibitors, such as tacrolimus, pimecrolimus, and cyclosporine;

[0173] (5) topical preparations of PDE4 inhibitors, such as apremilast, ibudilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, and crisabor;

[0174] (6) Topical preparations of JAK kinase inhibitors, such as tofacitinib, JTE-052, baricitinib, and upadacitinib;

[0175] (7) Topical nonsteroidal anti-inflammatory drugs, such as WBI-1001 and MRX-6;

[0176] (8) topical ROR agents, such as GSK2981278;

[0177] (9) Injectable anti-IL4, IL-31, IL-22, IL-33, IL-12, IL-23, IL-17, IgE, IL-4 therapeutic drugs, such as Dupilumab, Levitra, Nemolizumab, Tralokinumab, Etanercept, Adalimumab, Infliximab, Utekinumab, Secukinumab, Omazumilab, CIM-331;

[0178] (10) Vitamin D analogs, such as calcipotriol and calcitriol;

[0179] (11) Oral retinoic acid derivatives, such as alitretinoin;

[0180] (12) Oral liver X receptor (LXR) selective agonists, such as VTP-38543;

[0181] (13) Oral H4 receptor antagonists, such as ZPL-389;

[0182] (14) Oral NK1 receptor antagonists, such as aprepitant and trodipitant;

[0183] (15) Oral CRTH2 receptor antagonists, such as Fevipiprant and OC-459;

[0184] (16) Oral chymotrypsin inhibitors, such as SUN 13834.

[0185] Preferably, the compound represented by formula (I) or formula (II) alone or in combination with other active ingredients is administered for the prevention and / or treatment of respiratory diseases or skin inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), atopic dermatitis (AD) or psoriasis.

[0186] The treatment method comprising administering the compound or pharmaceutical composition of the present invention further comprises administering other anti-chronic obstructive pulmonary disease (COPD) or atopic dermatitis drugs (combination therapy) to the patient, wherein the other anti-chronic obstructive pulmonary disease (COPD) or atopic dermatitis drugs are the drugs among the above-mentioned additional therapeutic agents or their combinations.

[0187] The present invention provides a method for treating a lung disease (e.g., COPD, asthma or cystic fibrosis) or an inflammatory disease (e.g., atopic dermatitis or psoriasis) in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of at least one compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, and at least one compound selected from the group consisting of a steroid (e.g., a glucocorticoid), a calcineurin inhibitor, a PDE4 inhibitor, a JAK kinase inhibitor, a cysteinyl leukotriene antagonist, a nonsteroidal anti-inflammatory drug, a topical ROR agent, an anti-IL4 antibody, an IL-31 antibody, an IL-22 antibody, an IL-3 3 antibodies, IL-12 antibodies, IL-23 antibodies, IL-17 antibodies, IgE antibodies, IL-4 antibodies, vitamin D analogs, liver X receptor (LXR) selective agonists, histamine H1 antagonists, histamine H3 antagonists, H4 receptor antagonists, NK1 receptor antagonists, CRTH2 receptor antagonists, chymotrypsin inhibitors, 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists, α-adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, bronchodilators, PDE inhibitors.

[0188] Uses of the compounds and pharmaceutical compositions of the present invention

[0189] The amount of the compound of the invention or the compound in the composition of the invention can be effective to detectably antagonize PDE4 to treat the following diseases: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain and neuropathic pain), acute inflammation, chronic inflammation, psoriatic arthritis, rheumatoid arthritis, psoriasis, proliferative and inflammatory skin diseases (e.g., atopic dermatitis, seborrheic dermatitis, contact dermatitis), asthma, chronic obstructive pulmonary disease (COPD), arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram-negative sepsis, glomerulonephritis, Parkinson's disease, Alzheimer's disease, mild cognitive impairment (MCI), depression, anxiety, acute respiratory distress syndrome, osteoarthritis, ankylosing spondylitis, multiple sclerosis, gingivitis, periodontitis, pruritus, herpes, CNS tumors, interstitial pneumonia, allergy, crystal-induced arthritis, acute pancreatitis , chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, acute respiratory distress syndrome, pulmonary hypertension, gout, alcoholic liver disease, lupus, cancer, allergic rhinitis, non-allergic rhinitis, autoimmune hemolytic syndrome, autoimmune hepatitis, autoimmune neuropathy, cirrhosis, fibrotic diseases, gastritis, Goodpasture's syndrome, Graves' disease, Gullain-Barre disease, Hashimoto's thyroiditis, HIV-related autoimmune syndrome and blood diseases, lichen planus, myocarditis (including viral myocarditis), neuropathy (including, for example, IgA neuropathy, cell membrane neuropathy and idiopathic neuropathy), nephritic syndrome, Reiter's syndrome, Sjögren's syndrome, systemic lupus erythematosus, the method comprising administering to the patient an effective amount of at least one compound of formula (I) or formula (II) or a pharmaceutically acceptable salt or solvate thereof.

[0190] General synthetic steps

[0191] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I) or formula (II). The following reaction schemes and examples are provided to further illustrate the present invention.

[0192] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0193] In the examples described below, all temperatures are set in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. and Qingdao Ocean Chemical Factory.

[0194] Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0195] The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

[0196] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The test conditions for the H NMR spectrum were: at room temperature, a Bruker 400MHz or 600MHz NMR spectrometer, with CDC1 3 , d 6 -DMSO, CD 3 OD or d 6- Acetone is the solvent (reported in ppm), TMS (0 ppm) or chloroform (7.26 ppm) is used as the reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0197] The conditions for low-resolution mass spectrometry (MS) data determination were: Agilent 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1x 30 mm, 3.5 μm, 6 min, flow rate 0.6 mL / min, mobile phase: 5%-95% (CH 3 CN) in (H 2 O) with UV detection at 210 / 254 nm in electrospray ionization mode (ESI).

[0198] 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 model: NOVASEP, 50 / 80 mm, DAC), with UV detection at 210 nm / 254 nm.

[0199] The following abbreviations are used throughout this invention:

[0200] g gram; EtOH ethanol;

[0201] mg milligram; EtOAc ethyl acetate;

[0202] mol mole; EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0203] h hour; DMF N,N-dimethylformamide;

[0204] min minutes; DPPA diphenylphosphoryl azide;

[0205] L liter; HOAT N-hydroxy-7-azabenzotriazole;

[0206] mL,ml milliliter; IPA isopropyl alcohol;

[0207] M, mol / L mole / liter; KOAc potassium acetate, potassium acetate;

[0208] HPLC high performance liquid chromatography; MsCl methanesulfonyl chloride;

[0209] GC gas chromatography; Pd / C palladium carbon;

[0210] ACN acetonitrile; PE petroleum ether;

[0211] CD 3 OD deuterated methanol; Pd(dppf)Cl 2 [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride;

[0212] CDCl 3 Deuterated chloroform; THF Tetrahydrofuran;

[0213] CDI N,N'-Carbonyldiimidazole; TEA Triethylamine;

[0214] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene; TBAF tetrabutylammonium bromide;

[0215] DCM dichloromethane; Tf 2 O trifluoromethanesulfonic anhydride;

[0216] DIPEA N,N-diisopropylethylamine; 1,4-dioxane 1,4-dioxane;

[0217] DMSO dimethyl sulfoxide;

[0218] Synthesis method of intermediates:

[0219]

[0220] Important intermediates M-4, M-5 and M-6 can be prepared by the synthesis method of intermediates, wherein: represents a single bond or a double bond, R 1 , R 2 and R 4 The starting material M-1-1 undergoes a substitution reaction with trifluoromethanesulfonic anhydride to obtain an intermediate M-1, and the intermediate M-1 and the material M-1-2 are reacted with a coupling reagent (e.g., Pd(dppf)Cl 2 The intermediate M-2 is then reacted with the compound M-1-3 by a coupling reagent (e.g. Pd(dppf)Cl 2The intermediate M-3 is subjected to suzuki coupling reaction, the intermediate M-3 is subjected to catalytic hydrogenation reduction to obtain the intermediate M-4, the intermediate M-3 or the intermediate M-4 is deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to form the intermediate M-5, and the intermediate M-5 is subjected to condensation reaction with the compound M-1-4 under alkaline conditions (such as triethylamine, N,N-diisopropylethylamine, etc.) of a condensation reagent (such as EDCI and HOAT, etc.) to obtain the intermediate M-6.

[0221] Synthesis method of target product:

[0222] Synthesis method 1:

[0223]

[0224] The target compound S-3 can be prepared by synthetic method 1, wherein: represents a single bond or a double bond, R a1 =R a , R b1 =R b , or R a1 and R b1 Together with the nitrogen atom to which it is attached, it forms a 5-7 membered nitrogen-containing heterocyclic ring, unless otherwise specified. 1 , R 2 , R a and R b The compound S-1 is hydrolyzed under alkaline conditions (such as lithium hydroxide, potassium hydroxide, etc.) to obtain the compound S-2, and the compound S-2 and the compound S'-1 are condensed under the action of a suitable condensing agent (such as EDCI and HOAT, etc.) under alkaline conditions (such as triethylamine, N,N-diisopropylethylamine, etc.) to obtain the target compound S-3; wherein the preparation method of the compound S-1 is the same as the preparation method of the intermediate M-6.

[0225] Synthesis method 2:

[0226]

[0227] The target compound S-4 can be prepared by synthetic method 2, wherein: represents a single bond or a double bond, R 1 and R 2 Compound S-1 is reduced by a reduction reaction (for example, under the action of lithium borohydride) to obtain the target compound S-4. The preparation method of compound S-1 is the same as the preparation method of intermediate M-6.

[0228] Synthesis method three:

[0229]

[0230] The target compound S-12 can be prepared by synthetic method 3, wherein R 1 and R 2 The compound S-7 can be prepared by referring to the synthesis method of the compound M-4, and then the compound S-8 is obtained by reduction reaction under the condition of a reducing agent (such as lithium borohydride, etc.), the compound S-8 is subjected to a condensation reaction with MsCl under alkaline conditions (such as triethylamine, N, N-diisopropylethylamine, etc.) to obtain the compound S-9, the compound S-9 and the compound S'-2 are subjected to a substitution reaction under the condition of a suitable reagent (such as TBAF, etc.) to obtain the compound S-10, the compound S-10 is deprotected in an organic solvent of hydrogen chloride (such as ethyl acetate, isopropanol, etc.) to obtain the compound S-11, and the compound S-11 is subjected to a condensation reaction with the compound M-1-4 under alkaline conditions (such as triethylamine, N, N-diisopropylethylamine, etc.) to obtain the target compound S-12.

[0231] Synthesis method 4:

[0232]

[0233] The target compound S-16 can be prepared by synthetic method 4, wherein R 1 and R 2 Compound S-10 is subjected to oxidation reaction under strong base (e.g., potassium hydroxide, sodium hydroxide, etc.) to obtain compound S-13, compound S-13 is subjected to condensation reaction with ammonium chloride under condensation reagent (e.g., EDCI and HOAT, etc.) to obtain compound S-14, compound S-14 is deprotected in an organic solvent of hydrogen chloride (e.g., ethyl acetate, isopropanol, etc.) to obtain compound S-15, and compound S-15 is subjected to condensation reaction with acetic acid to obtain target compound S-16.

[0234] Synthesis method 5:

[0235]

[0236] The target compound S-19 can be prepared by synthetic method 5, wherein R 1 , R 2 and R 3It has the meaning as described in the present invention, and L is a leaving group (such as Cl-, etc.). Compound S-17 can be prepared according to the synthesis method of intermediate M-5, and then condensed with compound S'-3 under alkaline conditions (such as triethylamine, N,N-diisopropylethylamine, etc.) to obtain compound S-18, and compound S-18 is completely reduced or partially reduced under reducing agents (such as lithium borohydride, lithium aluminum tetrahydride, sodium borohydride, etc.) or hydrolyzed and reduced under alkaline conditions (such as lithium hydroxide) to obtain the target compound S-19.

[0237] Synthesis method six:

[0238]

[0239] The target compound S-21 can be prepared by synthetic method 6, wherein R 1 and R 2 Compound S-17 can be prepared according to the synthesis method of intermediate M-5, and then reacted with compound S'-4 under alkaline conditions (such as triethylamine, N,N-diisopropylethylamine, etc.) to obtain compound S-20, and compound S-20 is successively hydrolyzed and reduced to obtain target compound S-21.

[0240] Synthesis method seven:

[0241]

[0242] The target compound S-22 can be prepared by synthetic method 7, wherein R 1 , R 2 and R 3 Compound S-18 is subjected to a Grignard reaction to obtain the target compound S-22.

[0243] Synthesis method eight:

[0244]

[0245] The target compound S-23 can be prepared by synthetic method eight, wherein R 1 , R 2 and R 3 Compound S-18 is subjected to hydrolysis and condensation reactions to obtain the target compound S-23.

[0246] Synthesis method nine:

[0247]

[0248] The target compound S-27 can be prepared by synthetic method 9, wherein R1 and R 2 Compound S-8 is subjected to condensation reaction to obtain compound S-24, compound S-24 is deprotected in an organic solvent (such as ethyl acetate, isopropanol, etc.) containing hydrogen chloride to obtain compound S-25, compound S-25 is subjected to acylation reaction to obtain compound S-26, and compound S-26 is subjected to hydrolysis reaction under alkaline conditions to obtain target compound S-27.

[0249] Synthesis method ten:

[0250]

[0251] The target compound S-30 can be prepared by synthetic method 10, wherein R 1 and R 2 Compound S-25 is subjected to condensation reaction to obtain compound S-28, compound S-28 is subjected to hydrolysis reaction to obtain compound S-29, and compound S-29 is deprotected in an organic solvent (such as ethyl acetate, isopropanol, etc.) containing hydrogen chloride to obtain target compound S-30.

[0252] Synthesis method 11:

[0253]

[0254] The target compound S-35 can be prepared by synthetic method 11, wherein R 1 and R 2 Compound S-31 can be prepared according to the synthesis method of compound S-19, and then compound S-32 is obtained by halogenation reaction under the conditions of halogenation reagent (such as lithium bromide, potassium bromide, etc.), compound S-32 and sodium azide are subjected to azidation reaction to obtain compound S-33, compound S-33 is subjected to catalytic hydrogenation reduction to obtain compound S-34, and compound S-34 and compound S'-6 are subjected to condensation reaction under the conditions of condensation reagent to obtain target compound S-35.

[0255] Synthesis method twelve:

[0256]

[0257] The target compound S-39 can be prepared by synthetic method 12, wherein R a1 =R a , R b1 =R b Unless otherwise stated, R 1 , R 2 , R a and R bCompound S-34 and compound S'-7 undergo condensation reaction under condensation reagent conditions to obtain compound S-36, compound S-36 undergoes hydrolysis reaction under alkaline conditions to obtain compound S-37, compound S-37 and compound S'-1 undergo condensation reaction under condensation reagent conditions to obtain compound S-38, and compound S-38 is deprotected in an organic solvent of hydrogen chloride (such as 1,4-dioxane, etc.) to obtain the target compound S-39. Example

[0258] Example 1: (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid

[0259]

[0260] Step 1: Synthesis of the compound benzyl (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)carbamate

[0261] 3-(Cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (5.0 g, 19.4 mmol) was dissolved in toluene (25 mL), diphenylphosphoryl azide (5.0 mL, 23.0 mmol) and triethylamine (4.3 mL, 31.0 mmol) were added, and the mixture was reacted at room temperature for 1 h. Benzyl alcohol (3.0 mL, 29.0 mmol) was added, and the mixture was transferred to 90 °C and heated for 3 h. The solvent was removed by concentration under reduced pressure, and water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (25 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 The residue was dried, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to obtain 5.01 g of a white solid with a yield of 71%.

[0262] 1 H NMR (600 MHz, CDCl 3 ): δ(ppm)7.35–7.43(m,5H),7.09(d,J=8.6Hz,1H),6.65–6.69(m,1H),6.58(t,J F-H =75.8Hz,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);

[0263] MS(ESI,pos.ion)m / z:364.10[M+H] + .

[0264] Step 2: Synthesis of compound 3-(cyclopropylmethoxy)-4-(difluoromethoxy)aniline

[0265] Dissolve benzyl (3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)carbamate (145 mg, 0.45 mmol) in anhydrous methanol (6 mL), add palladium carbon (50 mg), exclude air, introduce hydrogen, and react at room temperature for 2 h. Use diatomaceous earth to filter out the catalyst, and concentrate the filtrate to obtain 102 mg of a light red liquid with a yield of 98%.

[0266] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 6.94 (d, J = 8.4Hz, 1H), 6.47 (t, J F-H =76.3Hz,1H),6.26(d,J=2.2Hz,1H),6.20(dd,J=8.4,2.4Hz,1H),3.80(d,J=6.8Hz,2H),1.25-1.31(m,1H),0.58-0.65(m,2H),0.30-0.35(m,2H);

[0267] MS(ESI,pos.ion)m / z:230.10[M+H] + .

[0268] Step 3: Synthesis of compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene

[0269] The compound (3-(cyclopropylmethoxy)-4-(difluoromethoxy)aniline hydrochloride (17 g, 64.0 mmol) was dissolved in 1,4-dioxane (85 mL) and water (30 mL). Concentrated hydrochloric acid (17 mL) was added below 0°C, the temperature was lowered to -15°C, a solution of sodium nitrite (5.3 g, 77.0 mmol) and water (15 mL) was added dropwise, the temperature was controlled between -15°C and -5°C, and the reaction was continued at 0°C for 40 min. A solution of potassium iodide (13.8 g, 83.1 mmol) and water (15 mL) was added, the temperature was controlled between -15°C and -5°C, after the addition was complete, the reaction was continued at 0°C for 2 h, water (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL×2). The organic phase was washed once with saturated sodium sulfite and anhydrous Na 2 SO 4 After drying and concentration under reduced pressure, 21 g of the target product was obtained as a light brown liquid with a yield of 96%.

[0270] 1 H NMR (400 MHz, CDCl 3): δ(ppm)7.21–7.27(m,2H),6.89(d,J=8.1Hz,1H),6.59(t,J F-H =75.2Hz,1H),3.84(d,J=6.9Hz,2H),1.23–1.29(m,1H),0.61–0.69(m,2H),0.32–0.40(m,2H).

[0271] GC-MS m / z:340.0.

[0272] Step 4: Synthesis of compound (S)-1-tert-butyl-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate

[0273] The compound Boc-4-oxo-L-proline methyl ester (5.0 g, 20.6 mmol) was dissolved in dichloromethane (100 mL), cooled to -10 °C, N, N-diisopropylethylamine (17.0 mL, 103 mmol) was added, trifluoromethanesulfonic anhydride (9.9 g, 35 mmol) was slowly added dropwise, and the mixture was 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. Anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 10 / 1) to obtain 7.1 g of a light yellow oil with a yield of 92%.

[0274] 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).

[0275] MS(ESI,pos.ion)m / z:320.90[M-55] + .

[0276] Step 5: Synthesis of compound (S)-1-tert-butyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate

[0277] (S)-1-tert-Butyl-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (2.9 g, 7.7 mmol), biboronic acid pinacol ester (2.9 g, 11 mmol), potassium acetate (2.3 g, 23 mmol) and Pd(dppf)Cl 2 (50 mg, 0.068 mmol) was mixed in a 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. Water (30 mL) and ethyl acetate (50 mL) were added to the residue, stirred evenly, and the organic phase was separated. The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to obtain 1.44 g of light brown liquid with a yield of 51%.

[0278] 1 H NMR (400MHz, 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).

[0279] Step 6: Synthesis of compound (S)-1-tert-butyl-2-methyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate

[0280] (S)-1-tert-Butyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (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 Pd(dppf)Cl 2 (110 mg, 0.15 mmol) was mixed in a dry 1,4-dioxane (25 mL) solution, reacted at 100 °C for 5 h under nitrogen protection, cooled to room temperature, concentrated, and the residue was added with water (20 mL) and ethyl acetate (30 mL). After stirring evenly, the organic phase was separated and the organic phase was combined with Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to obtain 576 mg of light brown liquid with a yield of 41%.

[0281] 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 F-H =75.4Hz,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).

[0282] MS(ESI,pos.ion)m / z:462.10[M+Na] + .

[0283] Step 7: Synthesis of compound (2S)-1-tert-butyl-2-methyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

[0284] Compound (S)-1-tert-butyl-2-methyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (263 mg, 0.6 mmol) was dissolved in methanol (8 mL), and Pd / C (54 mg) was added. The mixture was reacted with hydrogen at room temperature and pressure for 6 h. The mixture was filtered and the filtrate was concentrated to obtain 258 mg of a colorless liquid with a yield of 97%.

[0285] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.10(d,J=7.9Hz,1H),6.77–6.81(m,2H),6.59(t,J F-H =75.6Hz,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=6.7Hz,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).

[0286] MS(ESI,pos.ion)m / z:464.10[M+Na] + .

[0287] Step 8: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

[0288] Compound (2S)-1-tert-butyl-2-methyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (667-4) (252 mg, 0.57 mmol) was dissolved in dichloromethane (5 mL) solution, 4 mol / L HCl in ethyl acetate (5 mL) was added, stirred at room temperature for 30 min, and concentrated under reduced pressure to obtain 202 mg of colorless liquid, with a yield of 94%.

[0289] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.14(d,J=8.4Hz,1H),7.08(d,J=1.6Hz,1H),6.92(dd,J=8.3,1.6Hz,1H),6.76(t,J F-H =75.5Hz,1H),4.60–4.65(m,1H),3.94(d,J=6.9Hz,2H),3.90(s,3H),3.78–3.83(m,1H),3.63–3.73(m,1H),3.3 3–3.40(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).

[0290] MS(ESI,pos.ion)m / z:342.40[M+H-HCl] + .

[0291] Step 9: Synthesis of compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester

[0292] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid 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, acetyl chloride (70 mg, 0.8 mmol) was added dropwise in an ice bath, and the reaction was stopped after stirring at room temperature for 5.5 h. Water (10 mL) was added, and dichloromethane was extracted (10 mL×3). The organic phases were combined and washed with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 2 / 1) to obtain 176 mg of light brown liquid with a yield of 87%.

[0293] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.12(d,J=8.6Hz,1H),6.82(s,1H),6.78–6.82(m,1H),6.60(t,J F-H =75.5Hz,1H),4.45–4.49(m,1H),3.91–3.95(m,1H),3.86(d,J=6.9Hz,2H),3.77(s,3H),3.60(t,J=10.4Hz,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).

[0294] MS(ESI,pos.ion)m / z:384.15[M+H] + .

[0295] Step 10: Synthesis of compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid

[0296] Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (92 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL), lithium hydroxide monohydrate (51 mg, 1.22 mmol) and water (3 mL) were added, and the mixture was reacted at 45°C for 50 min, and dilute hydrochloric acid was added to adjust the pH to 1, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with anhydrous Na 2 SO 4The residue was dried and concentrated under reduced pressure to obtain 84 mg of a white solid with a yield of 94%.

[0297] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.12(d,J=8.1Hz,1H),7.05(d,J=1.5Hz,1H),6.88-6.93(m,1H),6.74(t,J F-H =74.9Hz,1H),4.43–4.47(m,1H),4.08–4.12(m,1H),3.94(d,J=6.8Hz,2H),3.58–3.63(m,1H),3.50–3.56(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).

[0298] MS(ESI,pos.ion)m / z:370.10[M+H] + .

[0299] Example 2: Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N,N-dimethylpyrrolidine-2-carboxamide

[0300]

[0301] Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (72 mg, 0.19 mmol), dimethylamine hydrochloride (161 mg, 1.94 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (189 mg, 0.99 mmol) and N-hydroxy-7-azabenzotriazole (39 mg, 0.29 mmol) were dissolved in dichloromethane (5 mL). N,N-diisopropylethylamine (0.5 mL, 3.0 mmol) was added dropwise to the solution at 0°C. The mixture was stirred at room temperature for 6 h, and water (20 mL) was added. The mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15 / 1) to obtain 59 mg of a light yellow liquid with a yield of 76%.

[0302] 1 H NMR (400 MHz, CDCl 3): δ(ppm)7.09(d,J=8.1Hz,1H),6.86(s,1H),6.83(d,J=8.2Hz,1H),6.59(t,J F-H =75.6Hz,1H),4.84–4.88(m,1H),3.88–3.92(m,1H),3.85(d,J=6.9Hz,2H),3.65–3.70(m,1H),3.30–3.39(m,1H),3.16(s,3H ),2.99(s,3H),2.52–2.58(m,1H),2.08(s,3H),2.02–2.12(m,1H),1.24–1.36(m,1H),0.61–0.67(m,2H),0.33–0.36(m,2H).

[0303] MS(ESI,pos.ion)m / z:397.50[M+H] + .

[0304] Example 3: Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid

[0305]

[0306] Step 1: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride

[0307] Compound (S)-1-tert-butyl-2-methyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (243 mg, 0.55 mmol) was dissolved in dichloromethane (3 mL) solution, 4 mol / L HCl in ethyl acetate (3 mL) was added, and the mixture was stirred at room temperature for 50 min. The solvent was removed to obtain 183 mg of a light yellow solid with a yield of 97%.

[0308] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.15(d,J=8.3Hz,1H),6.90–6.98(m,2H),6.65(t,J F-H=75.1Hz,1H),6.06(s,1H),5.46(s,1H),4.58–4.84(m,2H),3.90(s,2H) ,3.88(s,3H),1.28–1.32(m,1H),0.60–0.73(m,2H),0.33–0.41(m,2H);

[0309] MS(ESI,pos.ion)m / z:340.40[M+H-HCl] + .

[0310] Step 2: Synthesis of compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester

[0311] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride (183 mg, 0.5 mmol) was dissolved in tetrahydrofuran (5 mL), N,N-diisopropylethylamine (0.15 mL, 0.9 mmol) was added, acetyl chloride (0.1 mL, 1.0 mmol) was added dropwise at 0°C, and the reaction was stopped after stirring at room temperature for 5 h. 50 mL of water was added for washing, and then extracted with dichloromethane (10 mL×3). The organic phases were combined and washed with Na 2 SO 4 After drying, the concentrated solution was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to obtain 176 mg of light yellow liquid, with a yield of 86%.

[0312] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.20-7.23(m,1H),7.14–7.18(m,1H),7.06–7.09(m,1H),6.81(t,J F-H =75.3Hz,1H),6.27–6.32(m,1H),5.23–5.30(m,1H),4.82(d,J=1.9Hz,2H),3.96(d,J=6.9H z,2H),3.77(s,3H),2.22(s,3H),1.31–1.34(m,1H),0.63–0.67(m,2H),0.38–0.42(m,2H).

[0313] MS(ESI,pos.ion)m / z:382.10[M+H] + .

[0314] Step 3: Synthesis of compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid

[0315] Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (96 mg, 0.25 mmol) was dissolved in tetrahydrofuran (5 mL), lithium hydroxide monohydrate (43 mg, 1.01 mmol) and water (2 mL) were added, and the mixture was reacted at 45°C for 2 h. Dilute hydrochloric acid was added to adjust the pH to 1, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, 89 mg of white solid was obtained with a yield of 96%.

[0316] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.14–7.23(m,2H),7.05–7.11(m,1H),6.81(t,J F-H =75.4Hz,1H),6.29–6.37(m,1H),5.17–5.26(m,1H),4.81(s,2H),3.97(d,J=6. 8Hz,2H),2.23(s,3H),1.31–1.35(m,1H),0.61–0.68(m,2H),0.36–0.44(m,2H).

[0317] MS(ESI,pos.ion)m / z:368.10[M+H] + .

[0318] Example 4: Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-2-carboxamide

[0319]

[0320] Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (81 mg, 0.22 mmol), dimethylamine hydrochloride (73 mg, 0.89 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (85 mg, 0.44 mmol) and N-hydroxy-7-azabenzotriazole (65 mg, 0.47 mmol) were dissolved in dichloromethane (6 mL). N,N-diisopropylethylamine (0.3 mL, 2.0 mmol) was added dropwise to the solution at 0°C. The mixture was stirred at room temperature for 6 h, water (50 mL) was added, and the mixture was extracted with dichloromethane (5 mL×3). The organic phase was purified by filtration. 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain 75 mg of a white solid with a yield of 86%.

[0321] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.22 (s, 1H), 7.15 (d, J = 8.3Hz, 1H), 7.07 (d, J = 6.8Hz, 1H), 6.80 (t, J F-H =75.4Hz,1H),6.36(s,1H),5.66–5.78(m,1H),4.61–4.82(m,2H),3.96(d,J=6.8Hz,2H),3.30(d,J=7.7 Hz,3H),3.01(d,J=14.5Hz,3H),2.21(s,3H),1.28–1.33(m,1H),0.59–0.68(m,2H),0.35–0.45(m,2H).

[0322] MS(ESI,pos.ion)m / z:395.10[M+H] + .

[0323] Example 5: Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxamide

[0324]

[0325] Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (91 mg, 0.25 mmol), ammonium chloride (133 mg, 2.49 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (137 mg, 1.24 mmol) and N-hydroxy-7-azabenzotriazole (52 mg, 0.38 mmol) were dissolved in dichloromethane (10 mL). After cooling to 0°C, N,N-diisopropylethylamine (0.7 mL, 4.0 mmol) was added dropwise. The mixture was stirred at room temperature for 12 h, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to obtain 61 mg of a white solid with a yield of 67%.

[0326] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.05–7.12(m,2H),6.89–6.93(m,1H),6.73(t,J F-H =75.6Hz,1H),4.41–4.45(m,1H),4.05–4.10(m,1H),3.93(d,J=6.8Hz,2H),3.60–3.65(m,1H),3.43–3.52(m,1H ),2.64–2.70(m,1H),2.13(s,3H),2.03–2.09(m,1H),1.28–1.36(m,1H),0.62–0.66(m,2H),0.36–0.40(m,2H).

[0327] MS(ESI,pos.ion)m / z:369.05[M+H] + .

[0328] Example 6: Compound ((3R)-1-((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester

[0329]

[0330] Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (96 mg, 0.26 mmol), (R)-pyrrolidin-3-ylcarbamic acid methyl ester hydrochloride (73 mg, 0.41 mmol) and N-hydroxy-7-azabenzotriazole (59 mg, 0.43 mmol) were dissolved in dichloromethane (5 mL), cooled to 0°C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (267 mg, 1.39 mmol) and N,N-diisopropylethylamine (0.3 mL, 2.0 mmol) were added, stirred at room temperature for 5 h, water (15 mL) was added, extracted with dichloromethane (5 mL×3), and the organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain 91 mg of a white solid with a yield of 64%.

[0331] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.10(d,J=8.1Hz,1H),6.87–6.89(m,1H),6.84(d,J=8.0Hz,1H),6.60(t,J F-H =75.6Hz,1H),4.53–4.64(m,1H),4.26–4.34(m,1H),3.99–4.08(m,1H),3 .81–3.91(m,1H),3.86(d,J=6.8Hz,2H),3.56–3.78(m,2H),3.66(s,3H), 3.32–3.52(m,3H),2.45–2.55(m,1H),2.13–2.32(m,2H),2.08(s,3H),2. 00–2.12(m,1H),1.24–1.32(m,1H),0.62–0.66(m,2H),0.33–0.36(m,2H).

[0332] MS(ESI,pos.ion)m / z:496.20[M+H] + .

[0333] Example 7: Compound (2R)-4-((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl)-2-methylpiperazine-1-carboxylic acid methyl ester

[0334]

[0335] Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (105 mg, 0.28 mmol), (R)-2-methylpiperazine-1-carboxylic acid methyl ester hydrochloride (71 mg, 0.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (269 mg, 1.4 mmol) and N-hydroxy-7-azabenzotriazole (54 mg, 0.4 mmol) were dissolved in dichloromethane (5 mL). N,N-diisopropylethylamine (0.3 mL, 2.0 mmol) was added dropwise to the solution at 0°C. The mixture was stirred at room temperature for 5 h, water (15 mL) was added, and the mixture was extracted with dichloromethane (5 mL×3). The organic phase was purified by filtration with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain 126 mg of a white solid with a yield of 85%.

[0336] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.08–7.10(m,1H),6.86(s,1H),6.80–6.84(m,1H),6.59(t,J F-H =75.6Hz,1H),4.80–4.92(m,1H),4.30–4.39(m,2H),3.88–3.98(m,3H),3. 84–3.86(m,2H),3.65–3.75(m,1H),3.71(s,3H),3.33–3.54(m,2.5H),3.03 –3.23(m,1.5H),2.73–2.97(m,1H),2.46–2.63(m,1H),2.08–2.12(m,3H),1 .24–1.32(m,1H),1.08–1.18(m,3H),0.61–0.66(m,2H),0.32–0.36(m,2H).

[0337] MS(ESI,pos.ion)m / z:510.20[M+H] + .

[0338] Example 8: Compound (R)-1-(4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrol-1-yl)ethanone

[0339]

[0340] Step 1: Synthesis of compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester

[0341] Using Boc-4-oxo-D-proline methyl ester as the starting material, the title compound was prepared according to the method of Step 4 to Step 9 of Example 1 to obtain 186 mg of a light yellow liquid.

[0342] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.11(d,J=8.2Hz,1H),7.04(s,1H),6.90–6.94(m,1H),6.73(t,J F-H =70.7Hz,1H),4.42-4.50(m,1H),4.05–4.16(m,1H),3.93(d,J=6.8Hz,2H),3.76(d,J=7.7Hz,3H),3.47-3.63(m, 2H),2.66–2.75(m,1H),2.13(s,3H),2.01–2.07(m,1H),1.27–1.33(m,1H),0.62–0.67(m,2H),0.36–0.40(m,2H).

[0343] MS(ESI,pos.ion)m / z:384.20[M+H] + .

[0344] Step 2: Synthesis of compound (R)-1-(4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrol-1-yl)ethanone

[0345] Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (184 mg, 0.48 mmol) was dissolved in anhydrous ethanol (6 mL), and lithium borohydride (62 mg, 2.85 mmol) was added. The reaction was refluxed at 80°C for 3 h to stop the reaction. The solvent was removed, and 50 mL of water was added. The mixture was extracted with ethyl acetate (5 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 2) to obtain 131 mg of a white solid with a yield of 76%.

[0346] 1 H NMR (400MHz, CD 3OD): δ(ppm)7.03–7.13(m,2H),6.89–6.95(m,1H),6.73(t,J F-H =74.9Hz,1H),4.12–4.22(m,1H),3.95–4.05(m,2H),3.93(d,J=6.9Hz,2H),3.64–3.74(m,1H),3.34–3.49(m,2H ),2.38–2.50(m,1H),2.12(s,3H),2.01–2.10(m,1H),1.28–1.33(m,1H),0.62–0.68(m,2H),0.36–0.41(m,2H).

[0347] MS(ESI,pos.ion)m / z:356.10[M+H] + .

[0348] Example 9: Compound ((3R)-1-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl)pyrrolidin-3-yl)carbamic acid methyl ester

[0349]

[0350] Step 1: Synthesis of compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid

[0351] Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (426 mg, 1.1 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (4 mL), and lithium hydroxide monohydrate (203 mg, 4.8 mmol) was added. The reaction was stopped at 50°C for 3 h, and hydrochloric acid was added to adjust the solution pH to 1, and then extracted with ethyl acetate (5 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, 388 mg of colorless liquid was obtained with a yield of 95%.

[0352] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.12(d,J=8.1Hz,1H),7.05(d,J=1.5Hz,1H),6.878-6.93(m,1H),6.74(t,J F-H=74.9Hz,1H),4.43–4.47(m,1H),4.08–4.15(m,1H),3.94(d,J=6.8Hz,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).

[0353] MS(ESI,pos.ion)m / z:370.25[M+H] + .

[0354] Step 2: Synthesis of methyl ((3R)-1-((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carbonyl)pyrrolidin-3-yl)carbamate

[0355] Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (123 mg, 0.33 mmol), (R)-pyrrole-3-carbamic acid methyl ester (118 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). N,N-diisopropylethylamine (0.4 mL, 2.0 mmol) was added dropwise to the solution at 0°C. The mixture was stirred at room temperature for 21 h, and water (15 mL) was added. The mixture was extracted with dichloromethane (5 mL×3). The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15 / 1) to obtain 122 mg of a white solid with a yield of 73%.

[0356] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.07–7.12(m,2H),6.92–6.93(m,1H),6.74(t,J F-H=75.7Hz,1H),4.64–4.72(m,1H),4.17–4.30(m,1H),4.05–4.10(m,1H),3.93(d, J=6.8Hz,2H),3.70–3.84(m,1H),3.66(s,3H),3.57–3.64(m,2H),3.42–3.55(m, 2H),2.62–2.73(m,1H),2.21–2.29(m,1H),2.12(d,J=3.1Hz,3H),1.97–2.07(m, 2H),1.89–1.95(m,1H),1.28–1.34(m,1H),0.62–0.68(m,2H),0.36–0.40(m,2H).

[0357] MS(ESI,pos.ion)m / z:496.30[M+H] + .

[0358] Example 10: Compound (S)-1-(4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrol-1-yl)ethanone

[0359]

[0360] Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (665-2) (78 mg, 0.20 mmol) was dissolved in anhydrous ethanol (4 mL). Lithium borohydride (31 mg, 1.42 mmol) was added to the solution at 0°C. The reaction was continued at 75°C for 6 h. The reaction was stopped and 20 mL of ice water was added to quench the reaction. The solvent was removed and the mixture was extracted with ethyl acetate (5 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 2) to obtain 58 mg of a white solid with a yield of 80% and a purity of 98.59%.

[0361] 1 H NMR (400MHz, CD 3OD): δ(ppm)7.12–7.22(m,2H),7.06(d,J=7.9Hz,1H),6.79(t,J=75.5Hz,1H),6.29(d,J=10.6Hz,1H),4.55–4.76(m ,3H),3.90–4.02(m,3H),3.72–3.81(m,1H),2.20(s,3H),1.29-1.33(m,1H),0.61–0.70(m,2H),0.34–0.42(m,2H).

[0362] MS(ESI,pos.ion)m / z:354.40[M+H] + .

[0363] Example 11: Compound 1-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone

[0364]

[0365] Compound (2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (102 mg, 0.27 mmol) was dissolved in anhydrous ethanol (5 mL) and LiBH 4 (29 mg, 1.33 mmol), reflux at 80 ° C for 1 h, then cool to room temperature, add water (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, and use anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15:1) to obtain 66 mg of colorless liquid with a yield of 69%.

[0366] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.12 (d, J = 8.7Hz, 1H), 6.78-6.97 (m, 2H), 6.60 (t, J F-H=74.9Hz,1H),4.19–4.26(m,1H),3.85–3.92(m,1H),3.86(d,J=6.9Hz,2H),3.72–3.79(m,1H),3.63–3.68(m,1H),3.39–3.44(m,1H ),3.25–3.34(m,1H),3.40–3.48(m,1H),2.13(s,3H),1.63–1.72(m,1H),1.23–1.34(m,1H),0.63–0.68(m,2H),0.33–0.37(m,2H).

[0367] MS(ESI,pos.ion)m / z:356.10[M+H] + .

[0368] Example 12: Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid methyl ester

[0369]

[0370] Step 1: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylic acid dimethyl ester

[0371] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (70 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (0.16 mL, 0.97 mmol) was added. Methyl chloroformate (70 mg, 0.8 mmol) was added at 0°C. The reaction was stopped after stirring at room temperature for 12 h. Water (10 mL) was added, and dichloromethane was extracted (10 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 After drying, the concentrated solution was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to obtain 68 mg of colorless liquid with a yield of 91%.

[0372] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.10(d,J=8.6Hz,1H),6.77–6.79(m,2H),6.59(t,J F-H=73.6Hz,1H),4.37–4.45(m,1H),3.98–4.14(m,1H),3.85(d,J=6.9Hz,2H),3.70–3.77(m,6H),3.38–3.48(m,1H), 3.28–3.37(m,1H),2.63–2.75(m,1H),1.98–2.08(m,1H),1.22–1.33(m,1H),0.62–0.67(m,2H),0.33–0.37(m,2H).

[0373] MS(ESI,pos.ion)m / z:400.10[M+H] + .

[0374] Step 2: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methoxycarbonyl)pyrrolidine-2-carboxylic acid

[0375] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylic acid dimethyl ester (206 mg, 0.52 mmol) and lithium hydroxide monohydrate (108 mg, 2.57 mmol) were added to a mixed solvent of tetrahydrofuran (10 mL) and water (10 mL). The reaction was stopped at 55°C for 1 h, and dilute hydrochloric acid was added to adjust the pH to 1. Ethyl acetate was added for extraction (10 mL×3). The organic phase was separated and precipitated with anhydrous Na 2 SO 4 After drying, 191 mg of colorless liquid was obtained, with a yield of 96%.

[0376] MS(ESI,pos.ion)m / z:386.10[M+H] + .

[0377] Step 3: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid methyl ester

[0378] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(methoxycarbonyl)pyrrolidine-2-carboxylic acid (188 mg, 0.49 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and N,N'-carbonyldiimidazole (119 mg, 0.73 mmol) was added. The mixture was reacted at 60°C for 30 min and then cooled to room temperature. Sodium borohydride (95 mg, 2.38 mmol) was added in an ice bath. The reaction was stopped after 30 min. A saturated aqueous sodium chloride solution (10 mL) was added, and the pH was adjusted to 4 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with anhydrous Na 2SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to obtain 103 mg of colorless liquid with a yield of 57% and a purity of 89.59%.

[0379] 1 H NMR (600MHz, CD 3 OD): δ(ppm)7.09(d,J=8.2Hz,1H),7.04(s,1H),6.90(d,J=7.8Hz,1H),6.73(t,J F-H =75.8Hz,1H),3.99–4.04(m,3H),3.92(d,J=6.9Hz,2H),3.69–3.74(m,1H),3.72(s,3H),3.22–3.29(m ,2H),2.39–2.48(m,1H),2.04–2.20(m,1H),1.26–1.34(m,1H),0.62–0.66(m,2H),0.37–0.40(m,2H).

[0380] MS(ESI,pos.ion)m / z:372.45[M+H] + .

[0381] Example 13: Compound Cyclopropyl ((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone

[0382]

[0383] Step 1: Synthesis of compound (2S)-1-(cyclopropanecarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester

[0384] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (74 mg, 0.20 mmol), cyclopropylcarboxylic acid (87 mg, 1.11 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg, 0.98 mmol) and N-hydroxy-7-azabenzotriazole (41 mg, 0.30 mmol) were dissolved in dichloromethane (5 mL), N,N-diisopropylethylamine (0.2 mL, 1.0 mmol) was added dropwise in an ice bath, stirred at room temperature overnight, water (20 mL) was added, extracted with dichloromethane (10 mL×3), and the organic phase was washed with anhydrous Na 2 SO 4After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 2 / 1) to obtain 67 mg of a white solid with a yield of 83%.

[0385] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.15(d,J=7.9Hz,1H),6.87(s,1H),6.82–6.85(m,1H),6.63(t,J F-H =75.6Hz,1H),4.48–4.52(m,1H),4.22–4.26(m,1H),3.89(d,J=6.8Hz,2H) ,3.78(s,3H),3.71–3.76(m,1H),3.41–3.51(m,1H),2.63–2.68(m,1H),2.0 2–2.13(m,1H),1.64–1.69(m,1H),1.27–1.36(m,1H),1.11–1.16(m,1H),0 .94–1.00(m,1H),0.80–0.84(m,2H),0.66–0.70(m,2H),0.37–0.40(m,2H).

[0386] MS(ESI,pos.ion)m / z:410.10[M+H] + .

[0387] Step 2: Synthesis of compound (2S)-1-(cyclopropanecarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid

[0388] Compound (2S)-1-(cyclopropylcarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (123 mg, 0.3 mmol) and lithium hydroxide monohydrate (63 mg, 1.5 mmol) were added to a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL), and the mixture was reacted at 55°C for 1 h. The reaction was stopped, and dilute hydrochloric acid was added to adjust the pH to 1. Ethyl acetate was added for extraction (10 mL×3). The organic phase was separated and precipitated with anhydrous Na 2 SO 4 After drying, 119 mg of colorless liquid was obtained, with a yield of 100%.

[0389] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.08–7.13(m,2H),6.93–6.95(m,1H),6.93(t,J F-H=75.6Hz,1H),4.44–4.48(m,1H),4.34–4.38(m,1H),3.92–3.95(m,2H),3.70–3.75(m,1H),3.51–3.59(m,1H),3. 71–3.77(m,1H),2.01–2.10(m,2H),1.28–1.35(m,1H),0.84–0.92(m,4H),0.63–0.67(m,2H),0.37–0.41(m,2H).

[0390] MS(ESI,pos.ion)m / z:396.20[M+H] + .

[0391] Step 3: Synthesis of the compound cyclopropyl((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone

[0392] Compound (2S)-1-(cyclopropylcarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid (119 mg, 0.30 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and N,N'-carbonyldiimidazole (98 mg, 0.61 mmol) was added. The mixture was reacted at 60°C for 30 min and then cooled to room temperature. Sodium borohydride (35 mg, 0.88 mmol) was added under ice bath. The reaction was stopped after 30 min. A saturated aqueous sodium chloride solution (10 mL) was added. The pH value was adjusted to 4 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to obtain 48 mg of colorless liquid with a yield of 42%.

[0393] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.06–7.12(m,2H),6.92–6.96(m,1H),6.74(t,J F-H=75.6Hz,1H),4.27–4.34(m,1H),4.15–4.21(m,1H),3.94(d,J=6.9Hz,2H), 3.86–3.91(m,1H),3.67–3.71(m,1H),3.53–3.59(m,1H),3.33–3.42(m,1H), 2.42–2.48(m,1H),2.05–2.13(m,1H),1.82–1.93(m,1H),1.28–1.35(m,1H), 1.00–1.05(m,1H),0.80–0.93(m,3H),0.62–0.68(m,2H),0.37–0.41(m,2H).

[0394] MS(ESI,pos.ion)m / z:382.10[M+H] + .

[0395] Example 14: Compound ((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidin-2-yl)methanol

[0396]

[0397] Step 1: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxylic acid methyl ester

[0398] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (74 mg, 0.20 mmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (0.13 mL, 0.79 mmol) was added. 4-fluorobenzenesulfonyl chloride (113 mg, 0.58 mmol) was added at 0°C. The reaction was stopped after stirring at room temperature for 3 h. The organic phase was washed with aqueous solution (10 mL × 3). The organic phase was washed with anhydrous Na 2 SO 4 After drying, the concentrated solution was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to obtain 83 mg of colorless liquid, with a yield of 85%.

[0399] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.97-8.00(m,2H),7.24(t,J=8.6Hz,2H),7.09(d,J=8.1Hz,1H),6.71-6.75(m,2H),6.60(t,J F-H=75.5Hz,1H),4.50–4.54(m,1H),3.88–3.93(m,1H),3.84(d,J=6.9Hz,2H),3.78(s,3H),3.30–3.33(m,1H),3.1 4–3.23(m,1H),2.26–2.73(m,1H),2.08–2.16(m,1H),1.27-1.33(m,1H),0.64–0.69(m,2H),0.35–0.38(m,2H).

[0400] MS(ESI,pos.ion)m / z:500.00[M+H] + .

[0401] Step 2: Synthesis of the compound ((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidin-2-yl)methanol

[0402] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine-2-carboxylic acid methyl ester (76 mg, 0.15 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and LiAlH 4 (57 mg, 1.5 mmol), react for 30 min, stop the reaction, add saturated sodium chloride aqueous solution (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, and then use anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to obtain 48 mg of colorless liquid with a yield of 67%.

[0403] 1 H NMR (400MHz, CD 3 OD): δ(ppm)8.01-8.04(m,2H),7.41(t,J=8.7Hz,2H),7.04(d,J=8.2Hz,1H),6.88-6.89(m,1H),7.04(dd,J=8.2,1.6Hz,1H),6.70(t,J F-H=74.8Hz,1H),3.86–3.91(m,1H),3.88(d,J=6.8Hz,2H),3.77–3.84(m,3H),3.35–3.38(m,1H),2.53–2.6 2(m,1H),2.27–2.33(m,1H),2.01–2.09(m,1H),1.25–1.31(m,1H),0.61–0.65(m,2H),0.35–0.39(m,2H).

[0404] MS(ESI,pos.ion)m / z:472.50[M+H] + .

[0405] Example 15: Compound 2-((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetonitrile

[0406]

[0407] Step 1: Synthesis of compound (2S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0408] Compound (2S)-1-tert-butyl-2-methyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (2.0 g, 4.53 mmol) was dissolved in tetrahydrofuran (20 mL), and lithium borohydride (0.49 g, 22.65 mmol) was added. The mixture was reacted at room temperature for 4 h, filtered, concentrated, diluted with saturated sodium chloride solution (40 mL), extracted with ethyl acetate (10 mL×3), and anhydrous Na 2 SO 4 After drying and concentration, 1.68 g of colorless oily liquid was obtained with a yield of 90%.

[0409] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.10 (d, J = 8.4Hz, 1H), 6.78-6.81 (m, 2H), 6.59 (t, J F-H=75.7Hz,1H),5.17(d,J=8.3Hz,1H),4.02-4.09(m,1H),3.91-3.97(m,1H),3.86(d,J=6.8Hz,2H),3.74–3.79(m,1H),3.65–3.69(m, 1H),3.20–3.27(m,2H),2.36–2.41(m,1H),1.63–1.69(m,1H),1.48(s,9H),1.23–1.31(m,1H),0.62–0.67(m,2H),0.33–0.37(m,2H).

[0410] MS(ESI,pos.ion)m / z:436.30[M+Na] + .

[0411] Step 2: Synthesis of compound (2S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

[0412] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (105 mg, 0.242 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (0.15 mL, 0.484 mmol) was added. Methanesulfonyl chloride (0.05 mL, 0.363 mmol) was added under ice bath. After stirring for 10 min, the mixture was reacted at room temperature for 2 h. The reaction was stopped, and the mixture was washed with saturated sodium bicarbonate solution (5 mL) and water (5 mL). The organic phase was washed with anhydrous Na 2 SO 4 After drying, the concentrated solution was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to obtain 110 mg of light yellow oily liquid with a yield of 88%.

[0413] MS(ESI,pos.ion)m / z:514.00[M+Na] + .

[0414] Step 3: Synthesis of compound (2S)-2-(cyanomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0415] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (163 mg, 0.332 mmol) was dissolved in acetonitrile (7 mL), trimethylsilyl cyanide (66 mg, 0.663 mmol) and tetrabutylammonium fluoride (0.7 mL, 0.663 mmol) were added, and the mixture was reacted at 80°C for 3 h. The mixture was concentrated under reduced pressure to remove the solvent, and ethyl acetate (20 mL) was added to dissolve the mixture, and the mixture was washed with water (5 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 After drying, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5 / 1) to obtain 107 mg of colorless oily liquid with a yield of 94%.

[0416] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.12(d,J=8.0Hz,1H),6.81-6.87(m,2H),6.60(t,J F-H =75.6Hz,1H),4.02–4.09(m,1H),3.94-3.99(m,1H),3.87(d,J=6.6Hz,2H),3.17–3.34(m,2H),2.76–2.81(m,1H),2.56-2 .64(m,1H),2.20–2.24(m,1H),2.01–2.04(m,1H),1.47(s,9H),1.23–1.31(m,1H),0.63–0.67(m,2H),0.34–0.38(m,2H).

[0417] MS(ESI,pos.ion)m / z:445.25[M+Na] + .

[0418] Step 4: Synthesis of compound 2-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetonitrile hydrochloride

[0419] Compound (2S)-tert-butyl 2-(cyanomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate (107 mg, 0.253 mmol) was dissolved in dichloromethane (4 mL), and a 4 mol / L hydrochloric acid solution in ethyl acetate (4 mL) was added. The mixture was stirred at room temperature for 2 h, and the solvent was removed to obtain 89 mg of a light yellow oily liquid with a yield of 97%.

[0420] MS(ESI,pos.ion)m / z:267.05[M-55]+ .

[0421] Step 5: Synthesis of compound 2-((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetonitrile

[0422] Compound 2-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetonitrile hydrochloride (89 mg, 0.248 mmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (0.25 mL, 1.5 mmol) was added. Acetyl chloride (60 mg, 0.76 mmol) was added dropwise at 0°C. The reaction was stopped after stirring at room temperature for 4 h. The organic phase was washed with water (10 mL × 3). The organic phase was washed with anhydrous Na 2 SO 4 After drying, the concentrate was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 2 / 1) to obtain 63 mg of light yellow oily liquid with a yield of 69% and a purity of 90.36%.

[0423] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.13(d,J=8.1Hz,1H),6.88(J=1.6Hz,1H),6.83-6.85(m,1H),6.61(t,J F-H =75.5Hz,1H),4.24–4.30(m,1H),3.89-3.94(m,1H),3.88(d,J=6.9Hz,2H),3.54-3.60(m,1H),3.26–3.37(m,2H),2.71-2 .76(m,1H),2.60–2.67(m,1H),2.12(s,3H),2.06–2.09(m,1H),1.23–1.31(m,1H),0.62–0.67(m,2H),0.34–0.38(m,2H).

[0424] MS(ESI,pos.ion)m / z:365.20[M+H] + .

[0425] Example 16: Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[0426]

[0427] Step 1: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-((2,4-difluorobenzyl)carbamoyl)pyrrolidine-2-carboxylic acid methyl ester

[0428] 2,4-Difluorobenzylamine (150 mg, 1.05 mmol) was dissolved in dry DMF (5 mL), and N,N'-carbonyldiimidazole (220 mg, 1.36 mmol) was added. The mixture was heated at 60 °C for 50 min and then cooled to room temperature. N,N-diisopropylethylamine (0.14 mL, 0.85 mmol) and (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (266 mg, 0.71 mmol) were added. The mixture was heated at 60 °C for 3 h and then stopped. Ice water (15 mL) was added and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with anhydrous Na 2 SO 4 After drying, the concentrate was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to obtain 293 mg of a white solid with a yield of 54%.

[0429] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.37–7.43(m,1H),7.12(d,J=7.9Hz,1H),6.78–6.88(m,4H),6.61(t,J F-H =75.6Hz,1H),4.47–4.53(m,2H),4.36–4.42(m,1H),3.87(d,J=6.9Hz,2H),3.78(s,3H),3.37–3.48(m ,2H),2.64–2.70(m,1H),2.08–2.16(m,1H),1.27–1.36(m,1H),0.65–0.69(m,2H),0.35–0.39(m,2H).

[0430] MS(ESI,pos.ion)m / z:511.60[M+H] + .

[0431] Step 2: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-((2,4-difluorobenzyl)carbamoyl)pyrrolidine-2-carboxylic acid

[0432] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-((2,4-difluorobenzyl)carbamoyl)pyrrolidine-2-carboxylic acid methyl ester (193 mg, 0.38 mmol) and lithium hydroxide monohydrate (78 mg, 1.86 mmol) were added to a mixed solution of tetrahydrofuran (5 mL) and water (5 mL). The reaction was stopped at 55°C for 1 h, and dilute hydrochloric acid was added to adjust the pH to 1. Ethyl acetate was added for extraction (10 mL×3). The organic phase was separated and precipitated with anhydrous Na 2 SO 4 After drying, 183 mg of colorless liquid was obtained, with a yield of 98%.

[0433] Compound 718-2: 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.41–7.47(m,1H),7.10(d,J=8.2Hz,1H),7.02–7.05(m,1H),6.89–6.94(m,3H),6.72(t,J F-H =75.6Hz,1H),4.35–4.51(m,3H),3.90–3.96(m,1H),3.93(d,J=6.8Hz,2H),3.40–3.54(m,2H), 2.71–2.78(m,1H),2.01–2.09(m,1H),1.24–1.31(m,1H),0.61–0.66(m,2H),0.36–0.41(m,2H).

[0434] MS(ESI,pos.ion)m / z:497.25[M+H] + .

[0435] Step 3: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[0436] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-((2,4-difluorobenzyl)carbamoyl)pyrrolidine-2-carboxylic acid (88 mg, 0.18 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and N,N'-carbonyldiimidazole (58 mg, 0.36 mmol) was added. The mixture was reacted at 60 °C for 30 min and then cooled to room temperature. NaBH was added under ice bath. 4 (35 mg, 0.88 mmol), the reaction was stopped after 30 min, saturated sodium chloride aqueous solution (10 mL) was added, pH was adjusted to 4 with dilute hydrochloric acid, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, and anhydrous Na2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 2 / 1) to obtain 22 mg of colorless liquid, with a yield of 25%.

[0437] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.36–7.42(m,1H),7.11(d,J=8.0Hz,1H),6.83–6.88(m,1H),6.77–6.80(m,3H),6.61(t,J F-H =75.6Hz,1H),4.44(d,J=5.6Hz,2H),4.25–4.31(m,1H),3.85–3.88(m,2H),3.63–3.79(m,3H),3.24–3.5 1(m,2H),2.13–2.24(m,1H),1.98–2.05(m,1H),1.27–1.36(m,1H),0.64–0.69(m,2H),0.35–0.38(m,2H).

[0438] MS(ESI,pos.ion)m / z:483.30[M+H] + .

[0439] Example 17: Compound ((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(cyclopropylmethyl)pyrrolidin-2-yl)methanol

[0440]

[0441] Compound (2S)-1-(cyclopropylcarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (103 mg, 0.25 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and LiAlH 4 (49 mg, 1.29 mmol), react for 30 min, stop the reaction, add saturated sodium chloride aqueous solution (10 mL), extract with ethyl acetate (10 mL × 3), combine the organic phases, and wash with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 40 / 1) to obtain 34 mg of colorless liquid with a yield of 36%.

[0442] 1 H NMR (600MHz, CD 3OD): δ(ppm)7.15(d,J=1.8Hz,1H),7.05(d,J=8.2Hz,1H),6.90(dd,J=8.2,1.8Hz,1H),6.71(t,J F-H =75.9Hz,1H),3.93(d,J=6.9Hz,2H),3.72–3.74(m,1H),3.60–3.63(m,1H),3.35 –3.39(m,1H),3.25–3.27(m,1H),3.00–3.03(m,1H),2.83–2.91(m,2H),2.40–2.4 5(m,1H),2.24–2.27(m,1H),1.73–1.79(m,1H),1.31-1.39(m,1H),0.95–1.01(m, 1H),0.63–0.66(m,2H),0.52–0.59(m,2H),0.38–0.40(m,2H),0.19–0.24(m,2H).

[0443] MS(ESI,pos.ion)m / z:368.20[M+H] + .

[0444] Example 18: Compound Cyclopropyl ((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methanone

[0445]

[0446] Compound (2S)-1-(cyclopropylcarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (101 mg, 0.25 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and 3.0 mol / L methylmagnesium bromide in ether (0.42 mL, 1.3 mmol) was added at 0°C. The mixture was reacted at room temperature for 2 h, and a saturated sodium chloride aqueous solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying, the concentrate was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to obtain 27 mg of colorless liquid with a yield of 27%.

[0447] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.16(d,J=8.7Hz,1H),6.82–6.85(m,2H),6.63(t,J F-H=75.5Hz,1H),4.32–4.36(m,1H),4.25–4.29(m,1H),3.90(d,J=6.9Hz,2H),3.47–3.53(m,1H),3.18–3.27(m,1H),2.46–2.52(m,1H),1.6 9–1.77(m,2H),1.28–1.34(m,1H),1.20(s,3H),1.16(s,3H),0.95–1.05(m,1H),0.81–0.91(m,3H),0.66–0.70(m,2H),0.36–0.40(m,2H).

[0448] MS(ESI,pos.ion)m / z:410.10[M+H] + .

[0449] Example 19: Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[0450]

[0451] Step 1: Synthesis of compound (2S)-tert-butyl-2-(acetoxymethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate

[0452] Compound (2S)-tert-butyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (660 mg, 1.60 mmol) was dissolved in dichloromethane (8 mL), and N,N-diisopropylethylamine (2.7 mL, 16 mmol) was added. The mixture was cooled in an ice bath, and acetyl chloride (600 mg, 7 mmol) was added. The reaction was stopped after stirring at room temperature for 5 h. The organic phase was washed with aqueous solution (10 mL × 3), and the organic phase was washed with anhydrous Na 2 SO 4 After drying, the concentrated solution was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 10 / 1) to obtain 451 mg of light brown liquid with a yield of 62%.

[0453] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.28 (s, 1H), 7.13 (d, J = 8.6Hz, 1H), 6.82 (s, 1H), 6.62 (t, J F-H=75.6Hz,1H),4.24–4.41(m,2H),4.00–4.16(m,2H),3.88(d,J=6.9Hz,2H),3.15–3.29(m,2H),2.47–2.54(m ,1H),2.09(s,3H),1.86–2.01(m,1H),1.50(s,9H),1.27–1.37(m,1H),0.65–0.69(m,2H),0.35–0.39(m,2H).

[0454] MS(ESI,pos.ion)m / z:478.20[M+Na] + .

[0455] Step 3: Synthesis of compound ((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl acetate hydrochloride Dissolve compound (2S)-tert-butyl-2-(acetoxymethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate (450 mg, 0.99 mmol) in dichloromethane (5 mL) solution, add 4 mol / L HCl in ethyl acetate (5 mL), stir at room temperature for 2 h, remove the solvent, and obtain 376 mg of light yellow solid, with a yield of 97%.

[0456] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.15(d,J=8.2Hz,1H),7.09(s,1H),6.94(d,J=6.6Hz,1H),6.75(t,J F-H =75.6Hz,1H),4.48–4.52(m,1H),4.32–4.37(m,1H),4.04–4.13(m,1H),3.95(d,J=6.9Hz,2H),3.75–3.80(m,1H),3.60–3.70(m,1H) ),3.29–3.37(m,1H),2.54–2.61(m,1H),2.16(s,3H),1.93–2.03(m,1H),1.24–1.37(m,1H),0.63–0.68(m,2H),0.37–0.41(m,2H).

[0457] MS(ESI,pos.ion)m / z:356.10[M+H-HCl] + .

[0458] Step 4: Synthesis of ((2S)-1-carbamoyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl acetate

[0459] The compound ((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl acetate hydrochloride (450 mg, 0.99 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) solution, triethylamine (0.4 mL, 3.0 mmol) and trimethylsilyl isocyanate (0.2 mL, 2.0 mmol) were added under ice bath, and the reaction was stopped after 4 h at room temperature, and saturated sodium chloride aqueous solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). After the organic phases were combined, the organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to obtain 126 mg of colorless liquid with a yield of 62%.

[0460] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.28 (s, 1H), 7.14 (d, J = 8.6Hz, 1H), 6.82 (s, 1H), 6.62 (t, J F-H =75.6Hz,1H),4.78(br.s,2H),4.40–4.43(m,1H),4.10–4.20(m,3H),3.88(d,J=6.9Hz,2H),3.22–3.31(m,2H) ,2.58–2.63(m,1H),2.12(s,3H),1.86–1.94(m,1H),1.27–1.37(m,1H),0.65–0.70(m,2H),0.36–0.40(m,2H).

[0461] MS(ESI,pos.ion)m / z:399.15[M+H] + .

[0462] Step 5: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[0463] The compound ((2S)-1-carbamoyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl acetate (121 mg, 0.31 mmol) was dissolved in tetrahydrofuran (5 mL), lithium hydroxide monohydrate (66 mg, 1.57 mmol) and water (5 mL) were added, and the mixture was reacted at 50°C for 2 h, extracted with ethyl acetate (10 mL×3), and the organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain 76 mg of a white solid with a yield of 70%.

[0464] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.09(d,J=8.1Hz,1H),7.04(s,1H),6.91(d,J=7.9Hz,1H),6.73(t,J F-H =75.6Hz,1H),3.99–4.05(m,2H),3.93(d,J=6.8Hz,2H),3.79–3.83(m,1H),3.65–3.69(m,1H),3.23–3.3 3(m,2H),2.43–2.50(m,1H),1.87–1.96(m,1H),1.27–1.36(m,1H),0.62–0.66(m,2H),0.37–0.40(m,2H).

[0465] MS(ESI,pos.ion)m / z:357.10[M+H] + .

[0466] Example 20: Compound 2-amino-1-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone hydrochloride

[0467]

[0468] Step 1: Synthesis of intermediate Boc-glycine methyl ester

[0469] Glycine methyl ester hydrochloride (1.0 g, 8 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (3.1 mL, 17 mmol) was added. Boc-anhydride (2.2 mL, 9.6 mmol) was added dropwise to the solution at 0°C, and the mixture was stirred at room temperature for 12 h. The mixture was washed with water (20 mL), diluted hydrochloric acid solution (15 mL), and saturated sodium bicarbonate solution (10 mL). The organic phase was washed with anhydrous Na2 SO 4 After drying, the solvent was removed and the residue was concentrated to obtain 1.58 g of a colorless liquid with a yield of 100%.

[0470] MS(ESI,pos.ion)m / z:212.05[M+Na] + .

[0471] Step 2: Synthesis of intermediate Boc-glycine

[0472] The compound Boc-glycine (1.5 g, 7.9 mmol) was dissolved in tetrahydrofuran (10 mL), lithium hydroxide monohydrate (1.0 g, 24 mmol) and water (10 mL) were added, and the mixture was reacted at 50 °C for 1 h. Dilute hydrochloric acid was added to adjust the pH to 1, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the white solid was concentrated to 1.3 g, with a yield of 93%.

[0473] MS(ESI,pos.ion)m / z:198.00[M+Na] + .

[0474] Step 3: Synthesis of ((2S)-1-(2-((tert-butyloxycarbonyl)amino)acetyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl acetate

[0475] Compound ((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl acetate hydrochloride (200 mg, 0.51 mmol), Boc-glycine (179 mg, 1.02 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (493 mg, 2.57 mmol) and N-hydroxy-7-azabenzotriazole (109 mg, 0.80 mmol) were dissolved in dichloromethane (5 mL). N,N-diisopropylethylamine (0.45 mL, 2.7 mmol) was added dropwise to the solution at 0°C. The mixture was stirred at room temperature for 12 h, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL×3). The organic phase was purified by filtration with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3 / 1) to obtain 162 mg of a white solid with a yield of 62%.

[0476] 1 H NMR (400 MHz, CDCl 3): δ(ppm)7.13(d,J=8.7Hz,1H),6.77–6.80(m,2H),6.61(t,J F-H =75.6Hz,1H),4.35–4.45(m,3H),3.99–4.04(m,1H),3.87(d,J=6.9Hz,2H),3.81–3.88(m,2H),3.22–3.32(m,2H),2.4 9–2.54(m,1H),2.07(s,3H),1.91–1.98(m,1H),1.45(s,9H),1.25–1.37(m,1H),0.64–0.69(m,2H),0.36–0.38(m,2H).

[0477] MS(ESI,pos.ion)m / z:535.15[M+Na] + .

[0478] Step 4: Synthesis of tert-butyl (2-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate

[0479] The compound ((2S)-1-(2-((tert-butoxycarbonyl)amino)acetyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl acetate (154 mg, 0.3 mmol) was dissolved in tetrahydrofuran (5 mL), lithium hydroxide monohydrate (66 mg, 1.57 mmol) and water (5 mL) were added, and the mixture was reacted at 50°C for 1 h, extracted with ethyl acetate (10 mL×3), and the organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 2 / 1) to obtain 79 mg of colorless liquid with a yield of 55%.

[0480] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.15(d,J=8.7Hz,1H),6.79–6.82(m,2H),6.63(t,J F-H=75.6Hz,1H),4.24–4.29(m,1H),3.99–4.05(m,1H),3.90–3.95(m,1H),3.89(d,J=6.9Hz,2H),3.83–3.90(m,2H),3.66–3.71(m,1H ),3.28–3.40(m,2H),2.45–2.51(m,1H),1.69–1.78(m,1H),1.48(s,9H),1.25–1.37(m,1H),0.66–0.71(m,2H),0.38–0.41(m,2H).

[0481] MS(ESI,pos.ion)m / z:493.20[M+Na] + .

[0482] Step 5: Synthesis of compound 2-amino-1-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone hydrochloride

[0483] The compound (tert-butyl 2-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (734-3) (74 mg, 0.99 mmol) was dissolved in dichloromethane (5 mL) solution, 4 mol / L HCl isopropanol solution (3 mL) was added, and the mixture was stirred at room temperature for 1.5 h. The solvent was removed to obtain 58 mg of a light yellow solid with a yield of 90%.

[0484] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.03–7.15(m,2H),6.94(d,J=7.5Hz,1H),6.74(t,J F-H =75.6Hz,1H),4.20–4.26(m,1H),3.99–4.06(m,2H),3.92–3.97(m,1H),3.94(d,J=6.9Hz,2H),3.79–3.83(m,1H),3.70–3.7 4(m,1H),3.34–3.42(m,2H),2.43–2.51(m,1H),2.07–2.16(m,1H),1.25–1.37(m,1H),0.63–0.67(m,2H),0.37–0.41(m,2H).

[0485] MS(ESI,pos.ion)m / z:371.25[M+H-HCl] + .

[0486] Example 21: Compound 1-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-hydroxyethanone

[0487]

[0488] Step 1: Synthesis of compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(2-ethoxy-2-oxoacetyl)pyrrolidine-2-carboxylic acid methyl ester

[0489] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (440 mg, 1.17 mmol) was dissolved in dichloromethane (6 mL), N,N-diisopropylethylamine (1.2 mL, 7.3 mmol) was added, and ethyl oxalyl chloride (526 mg, 3.85 mmol) was added dropwise at 0°C. The reaction was stopped after stirring at room temperature for 6 h. The organic phase was washed with water (10 mL × 3), and the organic phase was washed with anhydrous Na 2 SO 4 After drying, the concentrated solution was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 2 / 1) to obtain 456 mg of light brown liquid with a yield of 88%.

[0490] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.10-7.13(m,1H),6.80(d,J=7.9Hz,1H),6.79(s,1H),6.60(t,J F-H =75.6Hz,1H),5.00–5.04(m,0.5H),4.54–4.58(m,0.5H),4.29–4.35(m,3H), 3.85(d,J=6.9Hz,2H),3.78(s,1.5H),3.72(s,1.5H),3.70–3.75(m,0.5H),3 .52–3.58(m,0.5H),3.35–3.43(m,1H),2.67–2.86(m,1H),2.01–2.18(m,1H) ,1.35–1.38(m,3H),1.25–1.36(m,1H),0.63–0.68(m,2H),0.34–0.37(m,2H).

[0491] MS(ESI,pos.ion)m / z:442.15[M+H] + .

[0492] Step 2: Synthesis of compound 1-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-hydroxyethanone

[0493] Compound (2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1-(2-ethoxy-2-oxoacetyl)pyrrolidine-2-carboxylic acid methyl ester (223 mg, 0.51 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and LiBH was added. 4 (116 mg, 5.33 mmol), stirred at room temperature for 2 h, added with saturated sodium chloride aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: DCM / MeOH (v / v) = 40 / 1) to obtain 68 mg of colorless liquid with a yield of 36%.

[0494] 1 H NMR (400MHz, CD 3 OD): δ (ppm) 7.10 (d, J = 8.2Hz, 1H), 7.06 (s, 1H), 6.91-6.93 (m, 1H), 6.73 (t, J F-H =75.6Hz,1H),4.58(s,2H),4.12–4.28(m,3H),3.98–3.99(m,1H),3.98(d,J=6.9Hz,2H),3.87–3.90(m,1H),3.6 9–3.72(m,1H),2.41–2.47(m,1H),2.01–2.10(m,1H),1.25–1.36(m,1H),0.62–0.66(m,2H),0.37-0.40(m,2H).

[0495] MS(ESI,pos.ion)m / z:372.10[M+H] + .

[0496] Example 22: Compound 1-(3-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0497]

[0498] Step 1: Synthesis of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0499] The compound 1-tert-butyloxycarbonyl-3-pyrrolidone (1.01 g, 5.4 mmol) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (4.4 mL, 27.0 mmol) and trifluoromethanesulfonic anhydride (1.5 mL, 8.9 mmol) were slowly added at -15 °C. After stirring for 10 min at -15 °C, the mixture was transferred to room temperature for reaction. After 3 h, the reaction was stopped, water (50 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). Anhydrous Na 2 SO 4 The product was dried and concentrated, and the concentrate was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 15 / 1) to obtain 290 mg of a light yellow oily liquid with a yield of 17%.

[0500] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)5.70-5.75(m,1H),4.17–4.24(m,4H),1.49(s,9H).

[0501] MS(ESI,pos.ion)m / z:261.95[M-55] + .

[0502] Step 2: Synthesis of compound 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester

[0503] Compound 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (290 mg, 0.91 mmol), biboric acid pinacol ester (360 mg, 1.42 mmol), Pd(dppf)Cl 2 (40 mg, 0.05 mmol) and potassium acetate (450 mg, 4.58 mmol) were mixed in a dry 1,4-dioxane (10 mL) solution, reacted at 100 ° C overnight under nitrogen protection, cooled to room temperature, filtered, the filter cake was washed with dichloromethane (30 mL), the filtrate was combined, washed with water (5 mL × 3), and the organic phase was washed with anhydrous Na 2 SO 4 After drying, the concentrated solution was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 15 / 1) to obtain 203 mg of light yellow oily liquid with a yield of 75%.

[0504] 1 H NMR (400 MHz, CDCl 3): δ(ppm)6.41–6.46(m,1H),4.18–4.22(m,4H),1.45(s,9H),1.27(s,12H).

[0505] MS(ESI,pos.ion)m / z:318.10[M+Na] + .

[0506] Step 3: Synthesis of tert-butyl 3-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0507] Compound 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (200 mg, 0.68 mmol), 2-(cyclopropylmethoxy)-1-(difluoromethyl)-4-iodobenzene (290 mg, 0.85 mmol), Pd(dppf)Cl 2 (20 mg, 0.03 mmol), potassium phosphate (390 mg, 1.84 mmol) were mixed in a dry 1,4-dioxane (10 mL) solution, reacted at 100 ° C for 6 h under nitrogen protection, cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (10 mL). The filtrate was combined and washed with water (5 mL × 3), anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 20 / 1) to obtain 102 mg of a light yellow solid with a yield of 39%.

[0508] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.13(d,J=8.2Hz,1H),6.95-6.97(m,1H),6.89–6.92(m,1H),6.62(t,J F-H =75.5Hz,1H),6.07–6.10(m,1H),4.42–4.48(m,2H),4.30(d,J=17.8Hz,2H),3.85–3.90 (m,2H),1.51(d,J=6.2Hz,9H),1.23–1.31(m,1H),0.63–0.67(m,2H),0.34–0.38(m,2H).

[0509] MS(ESI,pos.ion)m / z:404.40[M+Na] + .

[0510] Step 4: Synthesis of tert-butyl 3-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate

[0511] The compound 3-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (100 mg, 0.26 mmol) was dissolved in anhydrous methanol (5 mL), and 10% palladium carbon (52 mg, 0.25 g / g) was added. The air in the bottle was evacuated, and hydrogen was introduced. The reaction was allowed to react overnight at room temperature. The reaction solution was filtered through diatomaceous earth and concentrated to obtain 95 mg of an oily liquid with a yield of 94%.

[0512] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.10(d,J=8.1Hz,1H),6.78–6.80(m,2H),6.59(t,J F-H =75.7Hz,1H),3.84–3.87(m,2H),3.73–3.77(m,1H),3.52–3.65(m,1H),3.37–3.43(m,1H),3.23–3.32(m,2H) ,2.20–2.24(m,1H),1.92–1.97(m,1H),1.47(s,9H),1.23–1.31(m,1H),0.62–0.66(m,2H),0.32–0.36(m,2H).

[0513] MS(ESI,pos.ion)m / z:406.25[M+Na] + .

[0514] Step 5: Synthesis of compound 3-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine

[0515] The compound tert-butyl 3-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate (100 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), and a 4 mol / L hydrochloric acid solution in ethyl acetate (2 mL) was added. The mixture was stirred at room temperature for 1 h, and the solvent was removed to obtain 70 mg of a colorless liquid with a yield of 90%.

[0516] MS(ESI,pos.ion)m / z:284.20[M+H] + .

[0517] Step 6: Synthesis of compound 1-(3-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0518] The compound 3-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine (70 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (0.15 mL, 0.91 mmol) was added. Acetyl chloride (0.1 mL, 1.0 mmol) was added dropwise at 0°C. The reaction was stopped after stirring at room temperature for 5 h. Dichloromethane (15 mL) was added, and the mixture was washed with water (10 mL×3). Anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 2) to obtain 40 mg of a light yellow oily liquid with a yield of 50%.

[0519] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.09–7.13(m,1H),6.79–6.81(m,2H),6.60(t,J F-H =75.7Hz,1H),3.84–3.87(m,2H),3.78-3.82(m,1H),3.63–3.67(m,1H),3.45–3.56(m,1H),3.30–3.41(m,2H),2.2 5–2.40(m,1H),2.07(d,J=5.0Hz,3H),1.92–2.02(m,1H),1.23–1.31(m,1H),0.62–0.66(m,2H),0.33–0.37(m,2H).

[0520] MS(ESI,pos.ion)m / z:326.20[M+H] + .

[0521] Example 23: Compound 2-((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetamide

[0522]

[0523] Step 1: Synthesis of compound 2-((2S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetic acid

[0524] Compound (2S)-2-(cyanomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (508 mg, 1.08 mmol) was dissolved in ethanol (13 mL) and water (6 mL), potassium hydroxide (650 mg, 11.6 mmol) was added, and the mixture was reacted in an oil bath at 85°C for 12 h. The reaction solution was concentrated, adjusted to pH = 1 with 1 mol / L dilute hydrochloric acid, extracted with dichloromethane (15 mL × 3), and anhydrous Na 2 SO 4 After drying and concentration, 510 mg of light yellow oily liquid was obtained, with a yield of 96%.

[0525] MS(ESI,pos.ion)m / z:464.30[M+Na] + .

[0526] Step 2: Synthesis of compound (2S)-2-(2-amino-2-oxoethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0527] Compound 2-((2S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetic acid (286 mg, 0.65 mmol), ammonium chloride (45 mg, 0.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (250 mg, 1.30 mmol) and N-hydroxy-7-azabenzotriazole (96 mg, 0.71 mmol) were dissolved in dichloromethane (8 mL). N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) was added dropwise to the solution at 0°C. The mixture was stirred at room temperature for 3 h, washed with water (10 mL×3), and the organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to obtain 210 mg of foamy solid, with a yield of 74%.

[0528] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.09(d,J=8.1Hz,1H),6.78–6.82(m,2H),6.59(t,J F-H=75.8Hz,1H),6.10(s,1H),5.38(s,1H),3.92–4.14(m,2H),3.86(d,J=6.8Hz,2H),3.16–3.24(m,2H),2.89–2.92(m ,1H),2.52–2.68(m,2H),2.12–2.21(m,1H),1.47(s,9H),1.23–1.31(m,1H),0.62–0.66(m,2H),0.33–0.37(m,2H).

[0529] MS(ESI,pos.ion)m / z:463.25[M+Na] + .

[0530] Step 3: Synthesis of compound 2-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetamide hydrochloride

[0531] Compound (2S)-2-(2-amino-2-oxoethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (210 mg, 0.48 mmol) was dissolved in dichloromethane (3 mL), and a 4 mol / L hydrochloric acid solution in ethyl acetate (3 mL) was added. The mixture was stirred at room temperature for 2 h, and the solvent was removed to obtain 159 mg of a light yellow oily liquid with a yield of 98%.

[0532] MS(ESI,pos.ion)m / z:341.20[M+H] + .

[0533] Step 4: Synthesis of compound 2-((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetamide

[0534] Compound 2-((2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetamide hydrochloride (97 mg, 0.26 mmol), acetic acid (30 mg, 0.50 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (98 mg, 0.51 mmol) and N-hydroxy-7-azabenzotriazole (40 mg, 0.29 mmol) were dissolved in dichloromethane (4 mL). N,N-diisopropylethylamine (0.13 mL, 0.79 mmol) was added dropwise to the solution at 0°C. The mixture was stirred at room temperature for 4 h, washed with water (10 mL×3), and the organic phase was purified by purifying with anhydrous Na 2 SO 4After drying and removing the solvent, the concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 2) to obtain 63 mg of colorless viscous liquid with a yield of 64%.

[0535] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.10(d,J=8.2Hz,1H),6.86(d,J=1.8Hz,1H),6.81–6.83(m,1H),6.59(t,J F-H =75.5Hz,1H),6.22(s,1H),5.47(s,1H),4.25–4.30(m,1H),3.87(d,J=6 .9Hz,2H),3.83–3.85(m,1H),3.41–3.46(m,1H),3.19–3.28(m,1H),2.8 7–2.91(m,1H),2.68–2.73(m,1H),2.56–2.63(m,1H),2.23–2.31(m,1H) ,2.08(s,3H),1.23–1.31(m,1H),0.62–0.67(m,2H),0.34–0.37(m,2H).

[0536] MS(ESI,pos.ion)m / z:383.10[M+H] + .

[0537] Example 24: Compound (2S)-N 1 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-2-amino-N 5 -ethyl-N 5 -Methylglutaramide hydrochloride

[0538]

[0539] Step 1: Synthesis of compound 1-((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone

[0540] Compound (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester (800 mg, 2.09 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL), lithium borohydride (445 mg, 20.9 mmol) was added in an ice bath, and ice water (15 mL) was added after reaction at room temperature for 4 h. After concentration, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed with dilute hydrochloric acid (15 mL×1) and saturated sodium chloride aqueous solution (15 mL×1). The organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, 655 mg of colorless liquid was obtained, with a yield of 88%.

[0541] 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.14 (d, J = 8.7Hz, 1H), 6.81 (s, 2H), 6.62 (t, J F-H =75.5Hz,1H),5.57–5.59(m,1H),4.22–4.28(m,1H),3.90–3.95(m,1H) ,3.89(d,J=6.9Hz,2H),3.76–3.82(m,1H),3.66–3.71(m,1H),3.44(t,J =10.8Hz,1H),3.26–3.36(m,1H),2.43–2.50(m,1H),2.15(s,3H),1.65 –1.74(m,1H),1.27–1.35(m,1H),0.65–0.70(m,2H),0.36–0.40(m,2H).

[0542] MS(ESI,pos.ion)m / z:356.25[M+H] + .

[0543] Step 2: Synthesis of compound 1-((2R)-2-(bromomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0544] The compound 1-((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (520 mg, 1.46 mmol) was dissolved in ethyl acetate (20 mL), triethylamine (525 mg, 5.19 mmol) was added, and methanesulfonyl chloride (301 mg, 2.63 mmol) was added in an ice bath. After reacting at room temperature for 2 h, lithium bromide (636 mg, 7.32 mmol) was added, and the reaction was continued at room temperature for 12 h. Water (30 mL) was added to stop the reaction, and the organic phase was separated and the organic phase was washed with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 146 mg of light yellow liquid with a yield of 23%.

[0545] 1 H NMR (400 MHz, CDCl 3 ): δ7.15(d,J=8.1Hz,1H),6.90(s,1H),6.88(d,J=8.2Hz,1H),6.63(t,J F-H =75.6Hz,1H),4.36–4.42(m,1H),4.17–4.21(m,1H),4.05–4.10(m,1H),3.90(d,J=6.9Hz,2H),3.69–3.72(m,1H),3.52(d,J=10.7Hz, 1H),3.26–3.36(m,1H),3.51–3.57(m,1H),2.15–2.24(m,1H),2.13(s,3H),1.28–1.38(m,1H),0.66–0.70(m,2H),0.36–0.41(m,2H).

[0546] MS(ESI,pos.ion)m / z:419.15[M+H] + .

[0547] Step 3: Synthesis of compound 1-((2R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0548] The compound 1-((2R)-2-(bromomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (250 mg, 0.60 mmol) was dissolved in DMF (3 mL), sodium azide (388 mg, 5.97 mmol) was added, and the mixture was heated at 90°C for 2.5 h, cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with anhydrous Na2 SO 4 The residue was dried and concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 60 / 1) to obtain 163 mg of light brown liquid. The yield was 71%.

[0549] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.16(d,J=8.4Hz,1H),6.87(s,1H),6.85(d,J=8.2Hz,1H),6.63(t,J F-H =75.6Hz,1H),4.27–4.33(m,1H),4.14–4.18(m,1H),3.88–3.94(m,1H),3.91(d,J=6.9Hz,2H),3.39–3.47(m,2H),3.25–3 .33(m,1H),2.42–2.48(m,1H),2.07–2.18(m,1H),2.13(s,3H),1.28–1.36(m,1H),0.66–0.71(m,2H),0.38–0.41(m,2H).

[0550] MS(ESI,pos.ion)m / z:381.20[M+H] + .

[0551] Step 4: Synthesis of compound 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0552] The compound 1-((2R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (2.7 g, 7.1 mmol) and triphenylphosphine (2.4 g, 9.2 mmol) were dissolved in a mixed solvent of tetrahydrofuran / water (v / v=3 / 1, 40 mL), reacted at 50°C for 4 h, concentrated under reduced pressure, extracted with ethyl acetate (10 mL×3), and the organic phase was washed with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15 / 1) to obtain 1.8 g of light brown liquid with a yield of 71%.

[0553] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.10(d,J=8.2Hz,1H),7.08(s,1H),6.93–6.95(m,1H),6.74(t,JF-H =75.8Hz,1H),4.06–4.13(m,1H),4.00–4.04(m,1H),3.94(d,J=6.9Hz,2H),3.46(d,J=10.8Hz,1H),3.30–3.36(m,1H),2.95 –3.05(m,2H),2.47–2.54(m,1H),2.13(s,3H),1.93–2.01(m,1H),1.29–1.35(m,1H),0.63–0.67(m,2H),0.37–0.41(m,2H).

[0554] MS(ESI,pos.ion)m / z:355.00[M+H] + .

[0555] Step 5: Synthesis of compound (4S)-5-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-4-((tert-butyloxycarbonyl)amino)-5-oxopentanoic acid methyl ester

[0556] Compound 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (300 mg, 0.85 mmol), N-Boc-L-glutamic acid 5-methyl ester (442 mg, 1.70 mmol), and N-hydroxy-7-azabenzotriazole (231 mg, 1.70 mmol) were dissolved in dichloromethane (8 mL). After cooling to 0°C, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (486 mg, 2.54 mmol) and N,N-diisopropylethylamine (550 mg, 4.26 mmol) were added. The mixture was reacted at room temperature for 11 h. The organic phase was washed with a saturated sodium chloride aqueous solution (15 mL). The organic phase was separated and the organic phase was washed with anhydrous Na 2 SO 4 The residue was dried, concentrated and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 365 mg of a light brown solid. The yield was 72%.

[0557] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.14(d,J=8.6Hz,1H),6.85(s,2H),6.62(t,J F-H=75.5Hz,1H),5.23–5.35(m,1H),4.12–4.25(m,2H),3.88–3.94(m,1H),3.89(d,J= 6.9Hz,2H),3.75–3.82(m,1H),3.70(s,3H),3.42(t,J=10.9Hz,1H),3.20–3.33(m, 2H),2.41–2.59(m,3H),2.16–2.23(m,1H),2.14(s,3H),1.90–2.00(m,1H),1.78–1 .87(m,1H),1.45(s,9H),1.27–1.34(m,1H),0.65–0.70(m,2H),0.37–0.40(m,2H).

[0558] MS(ESI,pos.ion)m / z:598.25[M+H] + .

[0559] Step 6: Synthesis of compound (4S)-5-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid

[0560] Compound (4S)-5-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-4-((tert-butyloxycarbonyl)amino)-5-oxopentanoic acid methyl ester (360 mg, 0.60 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (3 mL), lithium hydroxide monohydrate (126 mg, 3.00 mmol) was added, and the reaction was stopped after 4 h at room temperature. Dilute hydrochloric acid was added to adjust the solution pH to 1, the solvent was removed under reduced pressure, and the mixture was extracted with dichloromethane (10 mL×2). The organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, 351 mg of white solid was obtained with a yield of 99%.

[0561] MS(ESI,pos.ion)m / z:584.15[M+H] + .

[0562] Step 7: Synthesis of tert-butyl ((2S)-1-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-5-(ethyl(methyl)amino)-1,5-dioxopentan-2-yl)carbamate

[0563] Compound (4S)-5-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-4-((tert-butyloxycarbonyl)amino)-5-oxopentanoic acid (100 mg, 0.17 mmol), N-methylethylamine (50 mg, 0.85 mmol) and N-hydroxy-7-azabenzotriazole (46 mg, 0. 34mmol) was dissolved in dichloromethane (5mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (165mg, 0.86mmol) and N,N-diisopropylethylamine (110mg, 0.85mmol) were added in an ice bath, and the mixture was reacted at room temperature for 4h. Water (20mL) was added and stirred, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (5mL×2), and the organic phases were combined and the organic phase was washed with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain 77 mg of a white solid with a yield of 72%.

[0564] MS(ESI,pos.ion)m / z:625.15[M+H] + .

[0565] Step 8: Compound (2S)-N 1 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-2-amino-N 5 -ethyl-N 5 Synthesis of -methylglutaramide hydrochloride

[0566] The compound tert-butyl ((2S)-1-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-5-(ethyl(methyl)amino)-1,5-dioxopentan-2-yl)carbamate (70 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) solution, and a 1,4-dioxane solution of HCl (4 mol / L, 5 mL) was added. The mixture was reacted at room temperature for 1 h and concentrated under reduced pressure to obtain 62 mg of a white solid with a yield of 98%.

[0567] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.11(d,J=8.2Hz,1H),7.04–7.06(m,1H),6.94(d,J=8.1Hz,1H),6.74(t,J F-H=75.7Hz,1H),4.23–4.30(m,1H),4.01–4.07(m,1H),3.92–4.00(m,1H),3.94(d,J=6.8Hz,2H),3.70 –3.77(m,1H),3.62–3.67(m,1H),3.43–3.55(m,2H),3.35–3.43(m,2H),2.99(s,1.5H),2.92(s,1.5H ),2.53–2.67(m,2H),2.45–2.53(m,1H),2.02–2.10(m,1H),2.14(s,3H),1.88–1.96(m,1H),1.28–1 .35(m,1H),1.17(t,J=7.0Hz,1.5H),1.10(t,J=7.0Hz,1.5H),0.63–0.66(m,2H),0.38–0.40(m,2H).

[0568] MS(ESI,pos.ion)m / z:525.30[M+H-HCl] + .

[0569] Example 25: Compound (2R)-2-(acetylaminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)pyrrolidine-1-carboxamide

[0570]

[0571] Step 1: Synthesis of compound N-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)acetamide

[0572] The compound 1-((2R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (2.7 g, 7.1 mmol) and triphenylphosphine (2.4 g, 9.2 mmol) were dissolved in a mixed solvent of tetrahydrofuran / water (v / v) = 3 / 1 (40 mL), reacted at 50°C for 4 h, concentrated under reduced pressure, extracted with ethyl acetate (10 mL×3), and the organic phase was washed with anhydrous Na 2 SO 4 The organic phase was dried and allowed to stand for 48 h, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15 / 1) to obtain 194 mg of light brown liquid with a yield of 35%.

[0573] 1 H NMR (400 MHz, CDCl 3): δ(ppm)7.09(d,J=8.0Hz,1H),6.81(s,1H),6.78(d,J=6.8Hz,1H),6.59(t,J F-H =75.7Hz,1H),6.32(br.s,1H),3.86(d,J=6.9Hz,2H),3.54–3.61(m,1H),3.47–3.52(m,1H),3.37–3.42(m,1H),3.21–3.30(m,2H) ,2.88–2.93(m,1H),2.34–2.41(m,1H),1.99(s,3H),1.51–1.59(m,1H),1.24–1.32(m,1H),0.62–0.66(m,2H),0.33–0.37(m,2H).

[0574] MS(ESI,pos.ion)m / z:355.15[M+H] + .

[0575] Step 2: Synthesis of compound (2R)-2-(acetylaminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)pyrrolidine-1-carboxamide

[0576] The compound 2-hydroxymethyl-5-aminophenylboronic acid half ester (27 mg, 0.18 mmol) was dissolved in dry tetrahydrofuran (5 mL), and N,N-diisopropylethylamine (26 mg, 0.20 mmol) and 4-nitrophenyl chloroformate (37 mg, 0.18 mmol) were added. The reaction was carried out at room temperature for 1 h. N-(((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)acetamide (60 mg, 0.17 mmol) was added. The reaction was carried out at room temperature for 17 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 The residue was dried and concentrated, and the concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to obtain 28 mg of a white solid with a yield of 35%.

[0577] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.62(s,1H),7.59(d,J=7.8Hz,1H),7.44–7.46(m,1H),7.12(d,J=8.1Hz,1H),7.04(s,1H),6.91(s,1H),6.74(t,J F-H=75.7Hz,1H),5.04(s,2H),4.58–4.69(m,2H),4.16–4.23(m,1H),4.07–4.12(m,1H),3.94(d,J=6.7Hz,2H),3.66–3.69(m,1H), 3.33–3.46(m,1H),2.56–2.65(m,1H),1.92–2.04(m,1H),2.00(s,3H),1.30–1.39(m,1H),0.62–0.67(m,2H),0.36–0.41(m,2H).

[0578] MS(ESI,pos.ion)m / z:530.10[M+H] + .

[0579] Example 26: Compound 2-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)isoindoline-1,3-dione

[0580]

[0581] Step 1: Synthesis of compound (R)-1-tert-butyl-2-methyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate

[0582] Compound (R)-1-tert-butyl-2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (2.1 g, 5.9 mmol), 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene (5.8 g, 2.2 mmol), potassium phosphate (5.0 g, 24.0 mmol) and Pd(dppf)Cl 2 (88 mg, 0.12 mmol) was mixed in a dry 1,4-dioxane (20 mL) solution, and reacted at 100 °C for 5 h under nitrogen protection. The reaction solution was filtered, 20 mL of water was added to the filtrate, and extracted with ethyl acetate (15 mL × 3). The organic phase was combined with anhydrous Na 2 SO 4 The mixture was dried, the solvent was removed, and the residue was concentrated. The concentrate was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to obtain 2.1 g of a yellow-brown liquid with a yield of 74%.

[0583] 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 F-H =75.0Hz,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).

[0584] MS(ESI,pos.ion)m / z:498.20[M+Na] + .

[0585] Step 2: Synthesis of compound (R)-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride

[0586] The compound (R)-1-tert-butyl-2-methyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (2.3 g, 4.8 mmol) was dissolved in dichloromethane (5 mL) solution, 4 mol / L HCl 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 light yellow liquid with a yield of 100%.

[0587] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.48–7.50(m,2H),7.33–7.43(m,4H),7.23(d,J=8.3Hz,1H),7.12(dd,J=8.3,1.9Hz,1H),6.81(t,J F-H =74.8Hz,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).

[0588] MS(ESI,pos.ion)m / z:376.05[M+H-HCl] + .

[0589] Step 3: Synthesis of compound (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester

[0590] Compound (R)-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride (2.0 g, 4.9 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (4.0 mL, 24 mmol) was added. After cooling to 0°C, acetyl chloride (1.1 g, 14 mmol) was added. After stirring at room temperature for 3 h, the reaction was stopped, and water (20 mL × 3) was added and stirred. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with anhydrous Na 2 SO 4 The residue was dried, concentrated and separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 2) to obtain 1.8 g of light yellow liquid with a yield of 89%.

[0591] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.36–7.47(m,5H),7.20(d,J=8.2Hz,1H),7.05–7.06(m,1H),6.95(dd,J=8.3,1.9Hz,1H),6.61(t,J F-H =74.8Hz,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).

[0592] MS(ESI,pos.ion)m / z:418.60[M+H] + .

[0593] Step 4: Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid methyl ester

[0594] Compound (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (4.5 g, 11 mmol) was dissolved in methanol (30 mL), Pd / C (450 mg) was added, hydrogen was introduced, and the reaction was carried out at room temperature for 5 h. The catalyst was removed by filtration, and the filtrate was concentrated to obtain 3.1 g of light brown liquid with a yield of 87%.

[0595] 1 H NMR (400 MHz, CDCl 3): δ(ppm)7.10(d,J=8.3Hz,1H),6.96(d,J=1.9Hz,1H),6.79(dd,J=8.3,2.0Hz,1H),6.56(t,J F-H =73.7Hz,1H),4.48–4.53(m,1H),3.94–3.98(m,1H),3.78(s,3H),3.63(t,J=10. 5Hz,1H),3.38–3.47(m,1H),2.65–2.71(m,1H),2.14(s,3H),2.05–2.11(m,1H).

[0596] MS(ESI,pos.ion)m / z:330.00[M+H] + .

[0597] Step 5: Synthesis of compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester

[0598] Compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid methyl ester (1.3 g, 3.9 mmol) was dissolved in anhydrous DMF (10 mL), potassium carbonate (1.8 g, 13 mmol) and 2-iodopropane (1.5 g, 8.8 mmol) were added, and the mixture was heated at 80°C for 4 h. The solvent was removed under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed with anhydrous Na 2 SO 4 The residue was dried, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 1.5 g of light brown liquid with a yield of 100%.

[0599] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.14(d,J=8.1Hz,1H),6.87(s,1H),6.83(dd,J=8.0,1.9Hz,1H),6.56(t,J F-H =75.5Hz,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=6.0Hz,6H).

[0600] MS(ESI,pos.ion)m / z:372.30[M+H] + .

[0601] Step 6: Synthesis of compound 1-((2R)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone

[0602] Compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester (560 mg, 1.51 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL), lithium borohydride (320 mg, 15.0 mmol) was added in an ice bath, the reaction was stopped after 1 h at room temperature, saturated sodium chloride aqueous solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3), and the organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, 502 mg of colorless liquid was obtained, with a yield of 96%.

[0603] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.14(d,J=8.2Hz,1H),6.85(s,1H),6.81(dd,J=8.2,1.8Hz,1H),6.56(t,J F-H =75.5Hz,1H),4.55–4.61(m,1H),4.23–4.29(m,1H),3.91–3.94(m,1H),3.76–3.82(m,1H),3.67–3.72(m ,1H),3.44(t,J=10.8Hz,1H),2.44–2.51(m,1H),2.16(s,3H),1.65–1.74(m,1H),1.38(d,J=6.1Hz,6H).

[0604] MS(ESI,pos.ion)m / z:344.10[M+H] + .

[0605] Step 7: Synthesis of compound 1-((2R)-2-(bromomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone

[0606] The compound 1-((2R)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (493 mg, 1.44 mmol) was dissolved in ethyl acetate (20 mL), triethylamine (442 mg, 4.37 mmol) was added, and methanesulfonyl chloride (333 mg, 2.91 mmol) was added in an ice bath. After reacting at room temperature for 1 h, lithium bromide (1.26 g, 14.56 mmol) was added and reacted at room temperature for 8 h. Water (30 mL) was added to stop the reaction, and the organic phase was separated and the organic phase was washed with anhydrous Na 2 SO 4 After drying and removing the solvent, 376 mg of light yellow liquid was obtained, with a yield of 64%.

[0607] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.15(d,J=8.2Hz,1H),6.94(d,J=1.4Hz,1H),6.87(dd,J=8.1,1.5Hz,1H),6.57(t,J F-H =75.5Hz,1H),4.56–4.62(m,1H),4.36–4.43(m,1H),4.18–4.23(m,1H),3.88–3.93(m,1H),3.68–3.71(m,1H),3.5 2(d,J=10.7Hz,1H),3.26–3.36(m,1H),2.51–2.62(m,1H),2.13–2.22(m,1H),2.13(s,3H),1.39(d,J=6.0Hz,6H).

[0608] MS(ESI,pos.ion)m / z:408.15[M+H] + .

[0609] Step 8: Synthesis of compound 1-((2R)-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone

[0610] The compound 1-((2R)-2-(bromomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (320 mg, 0.79 mmol) was dissolved in DMF (5 mL), sodium azide (512 mg, 7.9 mmol) was added, and the mixture was heated at 80°C for 6 h. After cooling to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with anhydrous Na 2 SO 4The residue was dried and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 60 / 1) to obtain 223 mg of light brown liquid with a yield of 76%.

[0611] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.15(d,J=8.2Hz,1H),6.91(d,J=1.5Hz,1H),6.86(dd,J=8.2,1.7Hz,1H),6.57(t,J F-H =75.5Hz,1H),4.56–4.62(m,1H),4.28–4.34(m,1H),4.13–4.19(m,1H),3.91–3.95(m,1H),3.39–3.48(m,2H),3 .38–3.41(m,1H),3.26–3.33(m,1H),2.43–2.49(m,1H),2.09–2.18(m,1H),2.13(s,3H),1.39(d,J=6.1Hz,6H).

[0612] MS(ESI,pos.ion)m / z:369.20[M+H] + .

[0613] Step 9: Synthesis of compound 1-((2R)-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone

[0614] The compound 1-((2R)-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (220 mg, 0.60 mmol) was dissolved in methanol (8 mL), Pd / C (23 mg) was added, hydrogen was introduced, and the reaction was carried out at room temperature for 3 h. The catalyst was filtered out and the filtrate was concentrated to obtain 176 mg of colorless liquid with a yield of 86%.

[0615] 1 H NMR (400MHz, CD 3 OD): δ(ppm)7.08–7.12(m,2H),6.95(dd,J=8.2,1.7Hz,1H),6.69(t,J F-H=75.6Hz,1H),4.64–4.72(m,1H),4.07–4.14(m,1H),4.01–4.05(m,1H),3.46(d,J=10.8Hz,1H),2.97–3. 05(m,2H),2.62–2.67(m,1H),2.48–2.55(m,1H),2.13(s,3H),1.92–2.01(m,1H),1.36(d,J=6.0Hz,6H).

[0616] MS(ESI,pos.ion)m / z:343.10[M+H] + .

[0617] Step 10: Synthesis of compound 2-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)isoindoline-1,3-dione

[0618] Compound 1-((2R)-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (40 mg, 0.12 mmol), monomethyl phthalate (25 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg, 0.58 mmol) and N-hydroxy-7-azabenzotriazole (31 mg, 0.23 mmol) were dissolved in dichloromethane (5 mL). After cooling to 0°C, N,N-diisopropylethylamine (91 mg, 0.71 mmol) was added. The mixture was reacted at room temperature for 3 h, washed with water (10 mL) and stirred, extracted with dichloromethane (10 mL×3), the organic phases were combined, and washed with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 17 mg of a white viscous solid with a yield of 30%.

[0619] 1 H NMR (400 MHz, CDCl 3 ): δ(ppm)7.86–7.89(m,2H),7.72–7.79(m,2H),7.09(d,J=8.0Hz,1H),6.77–6.86(m,2H),6.53(t,J F-H=75.5Hz,1H),4.65–4.72(m,1H),4.49–4.58(m,1H),4.11–4.16(m,1H),3.87–3.99(m,2H),3.42(t,J= 10.8Hz,1H),3.21–3.30(m,1H),2.49–2.57(m,1H),2.07(s,3H),1.78–1.87(m,1H),1.33–1.37(m,6H).

[0620] MS(ESI,pos.ion)m / z:473.10[M+H] + .

[0621] Biological tests

[0622] Biological Example 1

[0623] The present invention uses the following method to conduct biological tests on the compounds of the present invention: (1) Using the BPS production kit (BPS, Cat. No. 60343), according to the instructions provided by the manufacturer, the fluorescence polarization method is used to detect the inhibitory effect of the compound on the PDE4B2 enzyme. (2) The PDE4B2 enzyme concentration is prepared to 83.33 pg / μL, and the final concentration is 27.78 pg / μL; the substrate FAM-Cyclic-3', 5'-AMP concentration is prepared to 300 nM, and the final reaction concentration is 100 nM. The enzyme and substrate dilutions are both diluted with the buffer PDE Assay buffer provided by the kit; the Binding Agent is diluted 100 times using the Binding Agent Diluent provided by the kit for standby use. The reaction system is shown in Table 1.

[0624] Table 1 IC of compounds against PDE4B2 enzyme 50 Testing system

[0625]

[0626]

[0627] A 384-well plate was used for detection. The experiment set up the test sample well, positive control well, negative control well and blank well. Each sample was tested for the inhibitory effect on the PDE4B2 enzyme concentration at 10 concentrations using double wells. The PDE4B2 enzyme and FAM-Cyclic-3',5'-AMP substrate reaction wells were used as positive controls, the FAM-Cyclic-3',5'-AMP substrate wells were used as negative controls, and the buffer wells were used as blank controls. After adding the corresponding samples, enzymes, substrates and buffers to each well in the order of Table 1, incubated in a constant temperature oven at 25°C for 1h, and then 15μL of the configured Binding Agent was added to each well. After shaking in a constant temperature oscillator at 25°C for 1h, the detection was performed using a PHERAstarFS multifunctional microplate reader (BMG) at a wavelength of FP485 / 525. The inhibitory effect of the compound on the PDE4B2 enzyme at different concentrations was plotted using Graph Pad Prism5 software to calculate the IC 50 .

[0628] The inhibitory effect of the compounds provided in the examples of the present invention on the PDE4B2 enzyme was determined according to the above method. It was found that the compounds of the present invention have an inhibitory effect on the PDE4B2 enzyme. The IC 50 The value is less than 1 μM; it is further found that the IC value of some of the compounds of the present invention for the inhibition of PDE4B2 enzyme 50 The value is less than 500 nM; it is further found that the IC of some of the compounds of the present invention for the inhibition of PDE4B2 enzyme 50 Specifically, the results of the determination of the inhibitory effect of some of the compounds of the present invention on the PDE4B2 enzyme are shown in Table 2.

[0629] Table 2 The results of the determination of the inhibitory effect of some compounds of the present invention on PDE4B2 enzyme

[0630] Example No. <![CDATA[IC 50 (nM)]]> Example No. <![CDATA[IC 50 (nM)]]> Example 7 470.2 Example 8 69.5 Embodiment 11 95 Embodiment 15 71.36 Embodiment 22 141.2 Embodiment 23 118.5 Embodiment 26 69.87 / /

[0631] Conclusion: The experiment proves that the compounds of the present invention generally have a high inhibitory effect on PDE4B2 enzyme in vitro; in particular, the compounds in Table 2 show significant inhibitory activity in the in vitro inhibition screening experiment on PDE4B2 enzyme.

[0632] It will be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments and may be embodied in other specific forms without departing from its essential characteristics. It is therefore contemplated that the embodiments are to be considered in all respects as illustrative and non-restrictive, and reference should be made to the appended claims rather than to the foregoing embodiments, and all changes within the meaning and range of equivalents of the appended claims are therefore included in the present invention.

[0633] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0634] Finally, it should be noted that there are other ways to implement the present invention. Accordingly, the embodiments of the present invention are described as examples, but are not limited to the contents described in the present invention, and may also be modified within the scope of the present invention or added to the claims. All publications or patents cited in the present invention will be used as references of the present invention.

Claims

1. A compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt of the compound represented by formula (I): in: Ring A is Each R1 and R2 is independently halogenated C 1-3 Alkyl or C 3-6 Cycloalkyl-C 1-3 Alkylene; R3 is C 1-4 Alkyl-C(═O)-, wherein R3 is optionally substituted by 1, 2 or 3 R6; Each R6 is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 1-4 Alkoxy; R4 is C 1-6 Alkyl or wherein R4 is optionally substituted by 1, 2 or 3 R7; Each R7 is independently deuterium, hydroxyl, amino, cyano, oxo (=O) or -C(=O)-NR a R b ; Each R a and R b are independently hydrogen, deuterium, C 1-6 Alkyl or halogenated C 1-6 alkyl; R5 is hydrogen or deuterium.

2. The compound according to claim 1, wherein each R1 and R2 is independently -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, cyclopropylmethylene, cyclopropylethylidene, cyclobutylmethylene, cyclobutylethylidene, cyclopentylmethylene, cyclopentylethylidene, cyclohexylmethylene or cyclohexylethylidene.

3. The compound according to claim 2, which is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt of the compound represented by formula (II): The A ring is 4. The compound according to claim 1 or 3, wherein R3 is CH3-C(=O)-, CH3CH2-C(=O)- or CH3(CH2)2-C(=O)-, wherein R3 is optionally substituted by 1, 2 or 3 R6; wherein each R6 is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, oxo (=O), methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CH2CH2F, -CH2CH2CHF2, -CH2Cl, -CHCl2, -CH2CH2Cl, -CH2CHCl2, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy.

5. The compound according to claim 1 or 3, wherein R4 is C 1-4 Alkyl or heteroaryl-C 1-4 Alkylene, wherein R4 is optionally substituted by 1, 2 or 3 R7; wherein each R7 is independently hydrogen, deuterium, hydroxyl, amino, cyano or -C(=O)-NR a R b .

6. The compound according to claim 1 or 3, wherein each R a and R b are independently hydrogen, deuterium, C 1-4 Alkyl or halogenated C 1-4 alkyl.

7. The compound according to claim 1 or 3, wherein R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or wherein R4 is optionally substituted by 1, 2 or 3 R7; wherein each R7 is independently deuterium, hydroxyl, amino, cyano, oxo (=O) or -C(=O)-NR a R b .

8. The compound according to claim 1 or 3, wherein each R a and R b are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F, -CHF2, -CH2CH2F, -CH2CHF2, -CH2CH2CH2F, -CH2CH2CHF2, -CH2Cl, -CHCl2, -CH2CH2Cl or -CH2CHCl2.

9. A compound having one of the following structures or a stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt of a compound having one of the following structures:

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, further comprising at least one of a pharmaceutically acceptable carrier, excipient, additive, adjuvant or vehicle; optionally, It further comprises an additional therapeutic agent, wherein the additional therapeutic agent is: sodium pyruvate, doxofylline, tetomilast, talukast, theophylline, formoterol, salmeterol, fluticasone propionate, rolipram, pyramist, cilomilast, indacaterol, olodaterol, mildestane, zilopentam, salbutamol, carmoxicillin, budesonide, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, furoate Mometasone, roflenide, ciclesonide, ipratropium, oxitropium, tiotropium, glycopyrrolate, umeclidinium, vilanterol, aclidinium, benralizumab, tralokinumab, revatolide, crisabor, fluocinolone acetate, desoximetasone, mometasone, triamcinolone, betamethasone, alclometasone, desonide, hydrocortisone, clobetasol, halofem Tasol, diflorasone, meproclofen, tacrolimus, pimecrolimus, tazarotene, cyclosporine, apremilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, ibudilast, tofacitinib, JTE-052, baricitinib, upadacitinib, WBI-1001, MRX-6, GSK2981278, durulumab, Lekin izumab, nimolizumab, troloxinumab, etanercept, adalimumab, infliximab, ustekinumab, secukinumab, omalizumab, CIM-331, golimumab and pegol, tocilizumab, calcipotriol, calcitriol, alitretinoin, VTP-38543, ZPL-389, aprepitant, trodipitant, fulvepiprant, OC-459, SUN 13834, SB-011, VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02, or a combination thereof.

11. Use of the compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate diseases associated with type 4 phosphodiesterase.

12. The use according to claim 11, wherein the disease associated with type 4 phosphodiesterase is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin dependent diabetes; The respiratory diseases are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculosis fibrosis, cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis; The inflammation described herein is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis.

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