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

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the field of medicine and specifically relates to substituted aza-5-membered ring compounds, pharmaceutical compositions containing the compounds, and their uses and methods of use in medicine. In particular, the compounds described herein are PDE4 inhibitors useful for treating 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 intracellular second messengers. They primarily participate in physiological activities such as energy metabolism, memory, immune response, vision, and olfaction through activation of protein kinase A (PKA) and protein kinase G (PKG) pathways. Regulation of their intracellular concentrations is primarily determined by the balance between synthesis by adenylate (guanylate) cyclase and hydrolysis by phosphodiesterases (PDEs). PDEs specifically use 3,5-cyclic nucleotides as substrates, catalyzing the hydrolysis of intracellular cGMP and cAMP to produce the corresponding inactive adenosine 5-phosphate, thereby affecting various metabolic functions. Therefore, inhibiting PDEs is a very effective way to induce many cellular activities, affecting the activation of inflammatory and immune cells and the contractile response of smooth muscle cells.

[0003] To date, 11 gene families of phosphodiesterases (PDEs) have been reported, each comprising multiple subfamilies. PDEs are distributed in multiple tissues, and their inhibitors have a wide range of physiological effects. PDE4, PDE7, and PDE8 primarily hydrolyze cAMP, while PDE5, PDE6, and PDE9 specifically hydrolyze cGMP. PDE1, PDE2, PDE3, PDE10, and PDE11 act on both cAMP and cGMP. PDE4 is primarily distributed in various inflammatory cells, and its tissue distribution suggests its close connection to the central nervous system and immune system. Its inhibitors could be used to treat a variety of diseases, including allergic and inflammatory disorders, diabetes, central nervous system disorders, and pain.

[0004] Currently, research on PDE4 is mainly focused on immune and inflammatory diseases. Many well-known pharmaceutical companies in the world have used 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 clinical application of first-generation PDE4 inhibitors is limited due to severe side effects such as nausea and vomiting. Second-generation PDE4 inhibitors include roflumilast and cilomilast. Roflumilast is used to treat COPD and also has some therapeutic effects on other inflammatory diseases, such as ulcerative colitis and Crohn's disease. The third-generation PDE4 inhibitor apremilast has been used to treat autoimmune diseases such as psoriasis and has fewer side effects and is more easily tolerated by patients. WO / 2000 / 064260 discloses that a 1% cream of the PDE4 inhibitor Ro 20-1724 is effective in treating psoriasis. WO 2000 / 009504 discloses another PDE4 inhibitor, CP-80633 (0.5% ointment), which significantly improves the clinical scores of atopic dermatitis (erythema, induration, and excoriation). However, there is still a clinical need for more PDE4 inhibitors that can effectively treat atopic dermatitis. Summary of the Invention

[0005] The following is a summary of some aspects of the present invention and is not intended to be limiting. These and other aspects are described in greater detail below. All references in this specification are incorporated herein by reference in their entirety. In the event of a discrepancy between the disclosure of this specification and a reference, the disclosure of this specification shall prevail.

[0006] The present invention provides a class of compounds having phosphodiesterase type 4 (PDE4) inhibitory activity, which are used to prepare drugs for preventing, treating or alleviating respiratory diseases, allergies, inflammation, central nervous system diseases or non-insulin-dependent diabetes mellitus associated with PDE4, such as chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculous fibrosis, cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; wherein bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis, bronchiolitis obliterans, allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis; the compounds of the present invention can effectively inhibit PDE4 and have excellent physicochemical properties and pharmacokinetic properties.

[0007] The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds or compositions to treat the above-mentioned diseases in mammals, especially humans.

[0008] Specifically:

[0009] In one aspect, the present invention relates to a compound as represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound as represented by formula (I).

[0010]

[0011] in:

[0012] R 1 and R 2 are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, heterocyclic group composed of 3-10 atoms, C 6-10 Aryl, heteroaryl composed of 5-10 atoms, C 3-8 Cycloalkyl-C 1-4 Alkylene, C 1-6 Alkyl-C(=O)-, C 3-8 Cycloalkyl-C(=O)-, heterocyclic-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkylene or heteroaryl-C1-4 alkylene;

[0013] X and X 1 are each independently a bond, -O-, -S-, -N(R c )-, -C(=O)- or -S(=O) t -;

[0014] R 3 For hydrogen, deuterium, carboxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 3-10 atoms, heteroaryl composed of 5-10 atoms, C 3-8 Cycloalkyl-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkylene, heterocyclic group composed of 3-10 atoms -C 1-4 Alkylene, heteroaryl-C 1-4 Alkylene, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-S(=O) t -、C 1-6 Alkoxy-C(=O)-, C 3-8 Cycloalkyl-C(=O)-, C 3-8 Cycloalkyl-S(=O) t -, heterocyclic group consisting of 3 to 10 atoms -C(=O)-, heterocyclic group consisting of 3 to 10 atoms -S(=O) t -, -C(=O)-NR d R e 、-S(=O) t -NR d R e 、C 6-10 Aryl-C(=O)-, heteroaryl-C(=O)-, C 6-10 Aryl-S(=O) t - or heteroaryl-S(=O) composed of 5-10 atoms t -, where R 3 Unsubstituted or replaced by 1, 2, 3 or 4 R 6 replaced by;

[0015] Each R 6 are independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, C 1-4 Alkyl, C 1-4Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino or C 1-4 Alkyl-C(=O)-N(R c )-;

[0016] R 4 -(CH2) m -L-(CH2) n -G;

[0017] L is a bond, -O-, -S-, or -NR x -、-NR x -C(=O)-, -NR x -S(=O) t -、-NR x -C(=O)-NR y -、-NR x -C(=O)-O-, -S(=O) t -, -C(=O)-, or -C(=O)-O-;

[0018] Preferably, L is -O-, -S-, or -NR x -、-NR x -C(=O)-, -NR x -S(=O) t -、-NR x -C(=O)-NR y -、-NR x -C(=O)-O-, -S(=O) t -, -C(=O)- or -C(=O)-O-, wherein -NR x -C(=O)-, -NR x -S(=O) t -、-NR x -C(=O)-NR y -and-NR x The left end of -C(=O)-O- is respectively connected with (CH2) m Connect the right end to (CH2) n Connect, the right end of -C(=O)-O- and (CH2) m Connect the left end to (CH2) n connect;

[0019] Among them, each R x and R y are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10Aryl, heterocyclic group composed of 3-10 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 3-10 atoms -C 1-6 Alkylene, heteroaryl-C 1-6 Alkylene, C 1-6 Alkyl-S(=O) t -、C 1-6 Alkyl-C(=O)- or C 1-6 Alkoxy-C(=O)-C 1-6 alkylene;

[0020] G is C 3-8 Cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-10 atoms or heteroaryl consisting of 5-10 atoms; wherein G is unsubstituted or replaced by 1, 2, 3 or 4 R 7 replaced by;

[0021] Each R 7 are independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)-NR a R b 、-S(=O) t -NR a R b 、C 1-6 Alkyl-C(=O)-N(R c )-、C 1-6 Alkyl-S(=O) t -N(R c )-、C 1-6 Alkoxy-C(=O)-N(R c )-、C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-S(=O) t -、C 1-6 Alkoxy-C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-10 atoms or heteroaryl group consisting of 5-10 atoms;

[0022] Each R a and R bare independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 3-10 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 3-10 atoms -C 1-6 Alkylene, heteroaryl-C 1-6 Alkylene, C 1-6 Alkyl-S(=O) t - or C 1-6 Alkyl-C(=O)-, wherein each R a and R b are independently unsubstituted or substituted by 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O)-NH2, C 1-6 Alkoxy C(=O)-, C 1-6 Alkyl-C(=O)-N(R c )-、C 1-6 Alkyl-S(=O) t -N(R c )-、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 substituted with an alkylamino group;

[0023] Each R d and R e are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 3-10 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 3-10 atoms -C 1-6 Alkylene, heteroaryl-C 1-6 Alkylene, C 1-6 Alkyl-S(=O) t - or C 1-6 Alkyl-C(=O)-, wherein each R d and R eare independently unsubstituted or substituted by 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O)-NH2, C 1-6 Alkoxy C(=O)-, C 1-6 Alkyl-C(=O)-N(R c )-、C 1-6 Alkyl-S(=O) t -N(R c )-、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 substituted with an alkylamino group;

[0024] Each R c are independently hydrogen, deuterium, C 1-3 Alkyl or C 1-3 alkyl halide;

[0025] R is hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 alkyl halide;

[0026] R 5a 、R 5b 、R 6a and R 6b are independently hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 alkyl halide;

[0027] t is 1 or 2;

[0028] n is 0, 1, 2, 3 or 4;

[0029] m is 1, 2, 3 or 4.

[0030] In some embodiments, the compound of the present invention is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II):

[0031]

[0032] Among them, each R 1 、R 2 、R 3 、R5a 、R 5b 、R 6a 、R 6b , R, G, L and n have the meanings as defined in the present invention.

[0033] In some embodiments, the compound of the present invention is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (III):

[0034]

[0035] Among them, each R 1 、R 2 、R 3 、R 5a 、R 5b 、R 6a 、R 6b , R, G, IL and n have the meanings as defined in the present invention.

[0036] Some of the implementations are: 1 and R 2 are each independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, -CH=CH2, -CH2CH=CH2, -C≡CH, -CH2C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, cyclopropylethylene, cyclobutylmethylene, cyclobutylethylene, cyclopentylethylene, Methyl, cyclopentylethylene, cyclohexylmethylene, cyclohexylethylene, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C(=O)-, 1-3 Alkylene, naphthyl-C 1-3 Alkylene, pyridyl-C 1-3 Alkylene, pyrimidinyl-C 1-3 Alkylene, furyl-C 1-3 Alkylene, thienyl-C 1-3 Alkylene, pyrrolyl-C 1-3Alkylene, pyrazolyl-C 1-3 Alkylene, thiazolyl-C 1-3 Alkylene, oxazolyl-C 1-3 Alkylene, triazolyl-C 1-3 Alkylene, tetrazolyl-C 1-3 Alkylene, piperazinyl-C 1-3 Alkylene, piperidinyl-C 1-3 Alkylene, morpholinyl-C 1-3 Alkylene, thiomorpholinyl-C 1-3 Alkylene, tetrahydropyranyl-C 1-3 Alkylene or pyrrolidinyl-C 1-3 alkylene;

[0037] R 3 For hydrogen, deuterium, carboxyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, CH3-C(=O)-, CH3CH2-C(=O)-, CH3CH2CH2-C(=O)-, (CH3)2CH-C(=O)-, CH3-S(=O)2-, CH3CH2-S(=O)2-, CH3CH2CH2-S(=O)2-, (CH3)2CH-S(=O)2-, CH3-OC(=O)-, CH3CH2-OC(=O)-, CH3CH2CH2-OC(=O)-, (CH3)2CH-OC(=O)-, -S(=O)2-NH2 or -C(=O)-NH2, wherein R 3 Unsubstituted or replaced by 1, 2, 3 or 4 R 6 replaced by;

[0038] Each R 6 and -I, hydroxy, amino, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, methoxy, ethoxy, n-propyloxy, methylamino, ethylamino, or n-propylamino.

[0039] Some of the implementation schemes are that each R x and R y are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C 1-4 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-C 1-3 Alkylene, cyclobutyl-C 1-3Alkylene, cyclopentyl-C 1-3 Alkylene, cyclohexyl-C 1-3 Alkylene, phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C 1-3 Alkylene, naphthyl-C 1-3 Alkylene, pyridyl-C 1-3 Alkylene, pyrimidinyl-C 1-3 Alkylene, furyl-C 1-3 Alkylene, thienyl-C 1-3 Alkylene, pyrrolyl-C 1-3 Alkylene, pyrazolyl-C 1-3 Alkylene, thiazolyl-C 1-3 Alkylene, oxazolyl-C 1-3 Alkylene, triazolyl-C 1-3 Alkylene, tetrazolyl-C 1-3 Alkylene, piperazinyl-C 1-3 Alkylene, piperidinyl-C 1-3 Alkylene, morpholinyl-C 1-3 Alkylene, thiomorpholinyl-C 1-3 Alkylene, tetrahydropyranyl-C 1-3 Alkylene, pyrrolidinyl-C 1-3 Alkylene, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-C(=O)- or C 1-3 Alkoxy-C(=O)-C 1-3 Alkylene.

[0040] In some embodiments, G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein G is unsubstituted or replaced by 1, 2, 3 or 4 R 7 replaced by;

[0041] Each R 7 are independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, carboxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, -C(=O)-NR a R b 、-S(=O)2-NR a R b 、C 1-4 Alkyl-C(=O)-NH-, C1-4 Alkyl-S(=O)2-NH-, C 1-4 Alkoxy-C(=O)-NH-, CH3-C(=O)-, CH3CH2-C(=O)-, CH3CH2CH2-C(=O)-, (CH3)2CH-C(=O)-, CH3CH2CH2CH2- C(=O)-, CH3-S(=O)2-, CH3CH2-S(=O)2-, CH3CH2CH2-S(=O)2-, (CH3)2CH-S(=O)2-, CH3O-C(=O)-, CH3C H2O-C(=O)-、CH3CH2CH2O-C(=O)-、(CH3)2CHO-C(=O)-、CH3CH2CH2CH2O-C(=O)-、CH3-C(=O)-O-、CH3CH2-C(=O)-O-、CH3CH2CH2-C(=O)-O-、(CH3)2CH-C(=O)-O-、CH3CH2CH2CH2-C(=O)-O-、cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Among them, each R a and R b has the meaning as described in the present invention.

[0042] Some of the implementation schemes are that each R a and R b are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C 1-3 Alkylene, naphthyl-C 1-3 Alkylene, pyridyl-C 1-3 Alkylene, pyrimidinyl-C 1-3 Alkylene, furyl-C 1-3 Alkylene, thienyl-C 1-3 Alkylene, pyrrolyl-C 1-3 Alkylene, pyrazolyl-C 1-3 Alkylene, thiazolyl-C 1-3 Alkylene, oxazolyl-C 1-3 Alkylene, triazolyl-C 1-3 Alkylene, tetrazolyl-C 1-3 Alkylene, piperazinyl-C1-3 Alkylene, piperidinyl-C 1-3 Alkylene, morpholinyl-C 1-3 Alkylene, thiomorpholinyl-C 1-3 Alkylene, tetrahydropyranyl-C 1-3 Alkylene, pyrrolidinyl-C 1-3 Alkylene, C 1-3 Alkyl-S(=O)2- or C 1-3 Alkyl-C(=O)-; wherein each R a and R b are independently unsubstituted or substituted by 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O)-NH2, C 1-3 Alkoxy C(=O)-, C 1-3 Alkyl-C(=O)-NH-, C 1-3 Alkyl-S(=O) t -NH-, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, methoxy, ethoxy, n-propyloxy, isopropyloxy, N-methylamino, N-ethylamino, N'N-dimethylamino, N'N-diethylamino or N'N-methylethylamino.

[0043] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.

[0044] In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, additive, adjuvant and vehicle.

[0045] 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, pyramist, cilomilast, indacaterol, olodaterol, mildestan, zithromycin, salbutamol, carmoxicillin, budesonide, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, roflenide, ciclesonide, ipratropium bromide, oxitropium bromide, tiotropium bromide, glycopyrrolate, umeclidinium bromide, vilanterol, aclidinium bromide, benralizumab, tralokinumab, revavatropate, crisabor, fluocinonide, desoximetasone, mometasone, triamcinolone, betamethasone, alclometasone, desonide, hydrochloride Cortisone, clobetasol, halobetasol, diflorasone, meprobamate, tacrolimus, pimecrolimus, tazarotene, cyclosporine, apremilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, ibudilast, tofacitinib, JTE-052, baricitinib, upadacitinib, WBI-1001, MRX-6, GSK2981278, Dulu monoclonal antibody, levitra, nimolizumab, trovastatin, etanercept, adalimumab, infliximab, ustekinumab, secukinumab, omalizumab, CIM-331, golimumab and pegylated thiabendazole, tocilizumab, calcipotriol, calcitriol, alitretinoin, VTP-38543, ZPL-389, aprepitant, tredipitant, foviprant, OC-459, SUN 13834, SB-011, VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02, or a combination thereof.

[0046] In another aspect, the present invention provides use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate diseases associated with type 4 phosphodiesterase.

[0047] Some embodiments include the use of the present invention, wherein the disease associated with type 4 phosphodiesterase is respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin-dependent diabetes mellitus;

[0048] The respiratory diseases are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculous fibrosis, cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;

[0049] The inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis.

[0050] In another aspect, the present invention provides a method for preventing, treating or alleviating diseases associated with type 4 phosphodiesterase, comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition of the present invention.

[0051] Some embodiments include the method of the present invention, wherein the disease associated with type 4 phosphodiesterase is a respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin-dependent diabetes mellitus;

[0052] The respiratory diseases are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculous fibrosis, cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;

[0053] The inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis.

[0054] In another aspect, the present invention provides the compound or pharmaceutical composition of the present invention for use in preventing, treating or alleviating a phosphodiesterase type 4-related disease in a patient.

[0055] In some embodiments, the compound or pharmaceutical composition of the present invention is used to prevent, treat or alleviate a disease associated with type 4 phosphodiesterase in a patient, wherein the disease associated with type 4 phosphodiesterase is a respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin-dependent diabetes mellitus;

[0056] The respiratory diseases are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, bronchiectasis, tuberculous fibrosis, cystic fibrosis, acute respiratory distress syndrome or respiratory inflammation; bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis;

[0057] The inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis.

[0058] Another aspect of the present invention relates to methods for preparing, separating and purifying the compounds represented by formula (I), (II) or (III).

[0059] The foregoing description only summarizes certain aspects of the present invention, but is not intended to be limiting. These and other aspects will be described in more detail and fully below.

[0060] Detailed description of the present invention

[0061] Definitions and General Terms

[0062] Certain embodiments of the present invention will now be described in detail, with examples being illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all alternatives, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the 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.

[0063] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0064] 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.

[0065] 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.

[0066] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles 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., more than one component may be contemplated for use or use in implementing the described embodiments.

[0067] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., human, 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. As used herein, the term "patient" refers to a human (including adults and children or other animals). In some embodiments, a "patient" refers to a human.

[0068] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0069] 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, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0070] The term "chiral" refers to a molecule that is non-superimposable on its mirror image; whereas "achiral" refers to a molecule that is superimposable on its mirror image.

[0071] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0072] 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.

[0073] Stereochemical definitions and conventions used herein 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.

[0074] Many organic compounds exist in optically active forms, meaning they have the ability to rotate the plane of plane-polarized light. When 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 the compound, where (-) or l indicates that the compound is levorotatory and a compound prefixed with (+) or d indicates that the compound is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0075] 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.

[0076] Depending on the choice of starting materials and the process, the compounds of the present invention may exist as one of the possible isomers or a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0077] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0078] Any racemate of the resulting final product or intermediate can be separated into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separating 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).

[0079] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed 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 indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0080] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention.

[0081] In general, the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced with a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with one or more substituents selected from a specified group, the substituents may be the same or different at each position.

[0082] The term "optionally substituted with" means that the structure in question is unsubstituted or substituted with one or more substituents described herein. Substituents of the present invention 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—, carboxylalkoxy, NH2-C(═O)—, NH2-S(═O)2—, aryl-alkylene, heteroaryl-alkylene, heterocyclyl-alkylene, cycloalkyl-alkylene, and the like.

[0083] In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used in the present invention such as “each ... is independently”, “... is independently” and “... is independently” 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)-N(R p R q )" and the structural formula "-C 1-6 Alkylene-N(R p R q )" between the two p The specific options do not affect each other.

[0084] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C1-C6 alkyl" or "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0085] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be 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 a linking alkylene group or arylene group, respectively.

[0086] The term "alkyl" or "alkyl group" as used herein refers to a saturated, linear 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, hydroxyl, amino, carboxyl, azido, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo, haloalkyl, haloalkoxy, hydroxyl, In some embodiments, the alkyl group contains 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in yet other embodiments, the alkyl group contains 1 to 4 carbon atoms; and in still other embodiments, the alkyl group contains 1 to 3 carbon atoms.

[0087] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0088] The term "alkylene" refers to a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; in yet other embodiments, an alkylene group contains 1-3 carbon atoms; and in yet other embodiments, an alkylene group contains 1-2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0089] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2Double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including "cis" and "tans" positioning, or "E" and "Z" positioning. In some embodiments, the alkenyl group contains 2-8 carbon atoms; in other embodiments, the alkenyl group contains 2-6 carbon atoms; in yet other embodiments, the alkenyl group contains 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0090] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in yet other embodiments, the alkynyl group contains 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and the like.

[0091] The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", refers to -CO2H or -COOH.

[0092] The term "deuterium" refers to a single deuterium atom. For example, one deuterium atom replaces one hydrogen atom in a methyl group to form a mono-deuterated methyl group (-CDH2), two deuterium atoms replace two hydrogen atoms in a methyl group to form a di-deuterated methyl group (-CD2H), and three deuterium atoms replace three hydrogen atoms in a methyl group to form a tri-deuterated methyl group (-CD3).

[0093] As used herein, the term "unsaturated" means that the group contains one or more degrees of unsaturation.

[0094] The term "heteroatom" refers to O, S, N, P, B and Si, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring substituted with a hydrogen, 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).

[0095] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0096] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; and in yet other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein.

[0097] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), and the like.

[0098] The term "alkylamino" refers to an amino group (-NH2) in which two hydrogen atoms are independently optionally replaced with the same or different alkyl groups, including N-alkylamino and N'N-dialkylamino, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkylamino group contains 1-12 carbon atoms. In some embodiments, the alkylamino group contains 1-6 carbon atoms; in other embodiments, the alkylamino group contains 1-4 carbon atoms; in yet other embodiments, the alkylamino group contains 1-3 carbon atoms. The alkylamino group may be optionally substituted with one or more substituents described herein.

[0099] Examples of alkylamino groups include, but are not limited to, N-methylamino (-NHCH3), N-ethylamino (-NHCH2CH3), N'N-dimethylamino (-N(CH3)2), N'N-diethylamino (-N(CH2CH3)2), N'N-methylethylamino N'N-methylisopropylamino etc.

[0100] 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, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, and the like.

[0101] The term "jk atoms," where each j and k are independently any non-zero natural number, and k>j; "jk" includes j, k, and any natural number in between. Typically, this describes the number of ring atoms in a molecule, where 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.

[0102] The term "cycloalkyl" refers to a monovalent or multivalent saturated monocyclic, bicyclic, or tricyclic ring system containing 3-12 carbon atoms. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms; and in yet other embodiments, the cycloalkyl group contains 3-6 carbon atoms. The cycloalkyl group may be optionally substituted with one or more substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0103] The terms "cycloalkylalkyl" or "cycloalkyl-alkylene" are used interchangeably and refer to an alkyl group substituted with one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group have the meanings 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.

[0104] 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, phosphorus, sulfur, boron, and oxygen atoms. Unless otherwise specified, a heterocyclyl group can be a carbon group or a nitrogen group, and a -CH2- group can be optionally replaced by a -C(=O)- group. A sulfur atom of the ring can be optionally oxidized to an S-oxide. A nitrogen atom of the ring can be optionally oxidized to an N-oxide. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, and oxepanyl. Examples of heterocyclic groups in which the -CH2- group is replaced by -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 and 1,1-dioxothiomorpholinyl. The heterocyclic groups may be optionally substituted with one or more substituents described herein.

[0105] The terms "heterocyclylalkyl" and "heterocyclyl-alkylene" are used interchangeably to refer to an alkyl group substituted with a heterocyclyl group; wherein the heterocyclyl and alkyl groups have the meanings described herein. Examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-ylmethyl, pyrrolidin-2-ylmethyl, morpholin-4-ylmethyl, and the like.

[0106] 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 comprises a ring of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include phenyl, naphthyl, and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.

[0107] The terms "arylalkyl" or "aryl-alkylene" are used interchangeably to refer to an alkyl group substituted with one or more aryl groups, wherein the aryl and alkyl groups have the meanings described herein. In some embodiments, the arylalkyl group refers to a "lower arylalkyl" group, i.e., an aryl group attached to a C 1-6 In some other embodiments, the arylalkyl group refers to an alkyl or alkylene group containing C 1-4 "Phenylalkyl" of an alkyl group. Specific examples include diphenylmethyl, phenylmethylene, and phenylethylene. The aryl group on the arylalkyl or arylalkylene group may be further substituted with the substituents described herein.

[0108] 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," "heteroaromatic ring," or "heteroaromatic compound." The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, the 5-10 heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, N, or B.

[0109] 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 in no way 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.

[0110] 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.

[0111] As described herein, a ring system formed by a substituent group connected to a central ring by a bond (as shown in Formula C) represents that the substituent group can be substituted at any substitutable position on the ring. For example, Formula C represents that the substituent group R can be substituted mono- or poly-at any substitutable position on the C ring, as shown in Formulas C1-C19.

[0112]

[0113] As described herein, a linker attached to a ring system (as shown in Formula d) means that the linker can be attached to the rest of the molecule at any available position on the ring system. Formula d also means that any available position on the ring system can be attached to the rest of the molecule, as shown in Formulas d1 through d5.

[0114]

[0115] In the present invention, R 4 -(CH2) m -L-(CH2) n -G, wherein the left and right bonds of the L group are interchangeably connected to (CH2) m and (CH2) n For example, when L is -NR x -C(=O)-, -NR x -S(=O) t -、-NR x -C(=O)-NR y -or-NR x -C(=O)-O-, -(CH2) m -L-(CH2) n -G is defined as the left end connection of L (CH2) m At the same time, the right end of L is connected to (CH2) n , and connect to the left end of L (CH2) n At the same time, the right end of L is connected to (CH2) m There are two situations, the preferred solution is: when L is -NR x -C(=O)-, -NR x -S(=O) t -、-NR x -C(=O)-NR y -or-NRx -C(=O)-O-, the left end of L is connected to (CH2) m At the same time, the right end of L is connected to (CH2) n ; In addition, when L is -C(=O)-O-, -(CH2) m -L-(CH2) n -G is defined as -(CH2) m -C(=O)-OG and -(CH2) m -OC(=O)-(CH2) n -G two cases, wherein the preferred solution is when L is -C(=O)-O-, -(CH2) m -L-(CH2) n -G is defined as -(CH2) m -OC(=O)-G.

[0116] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by Formula (I) or Formula (II) in vivo. Such conversion is affected by the prodrug being hydrolyzed in the blood or converted to the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention may be an ester. In the prior art, 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 containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see 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.

[0117] "Metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0118] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or other methods described in the literature, such as ion exchange. 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 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0119] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0120] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, where one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. Available oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) can be used to treat the corresponding amine 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), where, for example, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0121] 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 (e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical composition is encompassed.

[0122] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0123] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic moiety using conventional chemical methods. Generally speaking, 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 generally carried out in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used where appropriate. Additional lists of suitable salts can be found, for example, in "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).

[0124] In addition, the compounds disclosed herein, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed herein can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms.

[0125] Any structural formula given herein is also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. 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 incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0126] 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 the context of radiotherapy of patients. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of Formula (I) or (II) can be prepared by conventional techniques familiar to those skilled in the art or by replacing the previously used unlabeled reagent with an appropriate isotopically labeled reagent as described in the Examples and preparations herein.

[0127] In addition, heavier isotopes, particularly deuterium (i.e. 2 Substitution with H or D) can provide certain therapeutic advantages resulting from greater metabolic stability. For example, this can result in an increased in vivo half-life, a reduced dosage requirement, or an improved therapeutic index. It should be understood that deuterium in the present invention is considered a substituent of the compound represented by Formula (I) or Formula (II). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. Where 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 according to the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, acetone-d6, DMSO-d6.

[0128] Description of the compounds of the present invention

[0129] The present invention relates to novel substituted nitrogen five-membered ring compounds and their use in medicine. The compounds of the present invention or pharmaceutical compositions containing the compounds are used as PDE4 inhibitors and have good therapeutic effects on atopic dermatitis.

[0130] In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I):

[0131]

[0132] Among them, each R 1 、R 2 、R 3 、R 4 、R 5a 、R 5b , RR 6a 、R 6b ,X,X 1 and R have the meanings described in the present invention.

[0133] Some of the implementations are: 1 and R 2 are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, heterocyclic group composed of 3-10 atoms, C 6-10 Aryl, heteroaryl composed of 5-10 atoms, C 3-8 Cycloalkyl-C 1-4 Alkylene, C 1-6 Alkyl-C(=O)-, C 3-8 Cycloalkyl-C(=O)-, heterocyclic-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkylene or heteroaryl-C 1-4 alkylene;

[0134] X and X 1 are each independently a bond, -O-, -S-, -N(R c )-, -C(=O)- or -S(=O) t -;

[0135] R 3 For hydrogen, deuterium, carboxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 3-10 atoms, heteroaryl composed of 5-10 atoms, C 3-8 Cycloalkyl-C 1-4 Alkylene, C 6-10 Aryl-C 1-4 Alkylene, heterocyclic group composed of 3-10 atoms -C 1-4 Alkylene, heteroaryl-C 1-4 Alkylene, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-S(=O) t -、C 1-6 Alkoxy-C(=O)-, C 3-8 Cycloalkyl-C(=O)-, C 3-8 Cycloalkyl-S(=O) t -, heterocyclic group consisting of 3 to 10 atoms -C(=O)-, heterocyclic group consisting of 3 to 10 atoms -S(=O) t -, -C(=O)-NR d R e 、-S(=O) t -NR d R e 、C 6-10 Aryl-C(=O)-, heteroaryl-C(=O)-, C 6-10 Aryl-S(=O) t - or heteroaryl-S(=O) composed of 5-10 atoms t -, where R 3 Unsubstituted or replaced by 1, 2, 3 or 4 R 6 replaced by;

[0136] Each R 6 are independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino or C 1-4 Alkyl-C(=O)-N(R c )-;

[0137] R 4 -(CH2) m -L-(CH2) n -G;

[0138] L is a bond, -O-, -S-, or -NRx -、-NR x -C(=O)-, -NR x -S(=O) t -、-NR x -C(=O)-NR y -、-NR x -C(=O)-O-, -S(=O) t -, -C(=O)-, -OC(=O)- or -C(=O)-O-;

[0139] Preferably, L is -O-, -S-, or -NR x -、-NR x -C(=O)-, -NR x -S(=O) t -、-NR x -C(=O)-NR y -、-NR x -C(=O)-O-, -S(=O) t -, -C(=O)- or -C(=O)-O-, wherein -NR x -C(=O)-, -NR x -S(=O) t -、-NR x -C(=O)-NR y -and-NR x The left end of -C(=O)-O- is respectively connected with (CH2) m Connect the right end to (CH2) n Connect, the right end of -C(=O)-O- and (CH2) m Connect the left end to (CH2) n connect;

[0140] Among them, each R x and R y are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 3-10 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 3-10 atoms -C 1-6 Alkylene, heteroaryl-C 1-6 Alkylene, C 1-6 Alkyl-S(=O) t -、C1-6 Alkyl-C(=O)- or C 1-6 Alkoxy-C(=O)-C 1-6 Alkylene; G is C 3-8 Cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3-10 atoms or heteroaryl consisting of 5-10 atoms; wherein G is unsubstituted or replaced by 1, 2, 3 or 4 R 7 replaced by;

[0141] Each R 7 are independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)-NR a R b 、-S(=O) t -NR a R b 、C 1-6 Alkyl-C(=O)-N(R c )-、C 1-6 Alkyl-S(=O) t -N(R c )-、C 1-6 Alkoxy-C(=O)-N(R c )-、C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-S(=O) t -、C 1-6 Alkoxy-C(=O)-, C 1-6 Alkyl-C(=O)-O-, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-10 atoms or heteroaryl group consisting of 5-10 atoms;

[0142] Each R a and R b are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 3-10 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 3-10 atoms -C 1-6 Alkylene, heteroaryl-C1-6 Alkylene, C 1-6 Alkyl-S(=O) t - or C 1-6 Alkyl-C(=O)-, wherein each R a and R b are independently unsubstituted or substituted by 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O)-NH2, C 1-6 Alkoxy C(=O)-, C 1-6 Alkyl-C(=O)-N(R c )-、C 1-6 Alkyl-S(=O) t -N(R c )-、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 substituted with an alkylamino group;

[0143] Each R d and R e are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group composed of 3-10 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 3-10 atoms -C 1-6 Alkylene, heteroaryl-C 1-6 Alkylene, C 1-6 Alkyl-S(=O) t - or C 1-6 Alkyl-C(=O)-, wherein each R d and R e are independently unsubstituted or substituted by 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O)-NH2, C 1-6 Alkoxy C(=O)-, C 1-6 Alkyl-C(=O)-N(R c )-、C 1-6 Alkyl-S(=O) t -N(R c )-、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4substituted with an alkylamino group;

[0144] Each R c are independently hydrogen, deuterium, C 1-3 Alkyl or C 1-3 alkyl halide;

[0145] R is hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 alkyl halide;

[0146] R 5a 、R 5b 、R 6a and R 6b are independently hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 alkyl halide;

[0147] t is 1 or 2;

[0148] n is 0, 1, 2, 3 or 4;

[0149] m is 1, 2, 3 or 4.

[0150] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II):

[0151]

[0152] Among them, each R 1 、R 2 、R 3 、R 5a 、R 5b 、R 6a 、R 6b , R, L, n and G have the meanings described in the present invention.

[0153] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (III) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (III):

[0154]

[0155] Among them, each R 1 、R 2 、R 3 、R 5a 、R 5b 、R 6a 、R 6b , R, G, L and n have the meanings as defined in the present invention.

[0156] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (IV) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or a prodrug thereof of the compound represented by formula (IV):

[0157]

[0158] Among them, each R 1 、R 2 、R 3 、R 5a 、R 5b 、R 6a 、R 6b , R, L, n and G have the meanings described in the present invention.

[0159] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (V) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (V):

[0160]

[0161] Among them, each R 1 、R 2 、R 3 、R 5a 、R 5b 、R 6a 、R 6b , R, G, L and n have the meanings as defined in the present invention.

[0162] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (VI) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (VI):

[0163]

[0164] Among them, each R 1 、R 2 、R 3、R 5a 、R 5b 、R 6a 、R 6b , R, G, L and n have the meanings as defined in the present invention.

[0165] In some embodiments, the present invention relates to a compound, which is a compound represented by formula (VII) or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (VII):

[0166]

[0167] Among them, each R 1 、R 2 、R 3 、R 5a 、R 5b 、R 6a 、R 6b , R, G, L and n have the meanings as defined in the present invention.

[0168] Some of the implementations are: 1 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, -CH=CH2, -CH2CH=CH2, -C≡CH, -CH2C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, cyclopropylethylidene, cyclobutylmethylene, cyclobutylethylidene, cyclopentylmethylene, Cyclopentylethylene, cyclohexylmethylene, cyclohexylethylene, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C 1-3 Alkylene, naphthyl-C 1-3 Alkylene, pyridyl-C 1-3 Alkylene, pyrimidinyl-C 1-3 Alkylene, furyl-C 1-3 Alkylene, thienyl-C 1-3 Alkylene, pyrrolyl-C 1-3 Alkylene, pyrazolyl-C1-3 Alkylene, thiazolyl-C 1-3 Alkylene, oxazolyl-C 1-3 Alkylene, triazolyl-C 1-3 Alkylene, tetrazolyl-C 1-3 Alkylene, piperazinyl-C 1-3 Alkylene, piperidinyl-C 1-3 Alkylene, morpholinyl-C 1-3 Alkylene, thiomorpholinyl-C 1-3 Alkylene, tetrahydropyranyl-C 1-3 Alkylene or pyrrolidinyl-C 1-3 Alkylene.

[0169] Some of the implementations are: 2 is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, -CH=CH2, -CH2CH=CH2, -C≡CH, -CH2C≡CH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, cyclopropylethylidene, cyclobutylmethylene, cyclobutylethylidene, cyclopentylmethylene, Cyclopentylethylene, cyclohexylmethylene, cyclohexylethylene, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, phenyl, naphthyl, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C 1-3 Alkylene, naphthyl-C 1-3 Alkylene, pyridyl-C 1-3 Alkylene, pyrimidinyl-C 1-3 Alkylene, furyl-C 1-3 Alkylene, thienyl-C 1-3 Alkylene, pyrrolyl-C 1-3 Alkylene, pyrazolyl-C 1-3 Alkylene, thiazolyl-C 1-3 Alkylene, oxazolyl-C 1-3 Alkylene, triazolyl-C 1-3 Alkylene, tetrazolyl-C 1-3 Alkylene, piperazinyl-C 1-3 Alkylene, piperidinyl-C 1-3 Alkylene, morpholinyl-C1-3 Alkylene, thiomorpholinyl-C 1-3 Alkylene, tetrahydropyranyl-C 1-3 Alkylene or pyrrolidinyl-C 1-3 Alkylene.

[0170] Some of the implementations are: 3 For hydrogen, deuterium, carboxyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, CH3-C(=O)-, CH3CH2-C(=O)-, CH3CH2CH2-C(=O)-, (CH3)2CH-C(=O)-, CH3-S(=O)2-, CH3CH2-S(=O)2-, CH3CH2CH2-S(=O)2-, (CH3)2CH-S(=O)2-, CH3-OC(=O)-, CH3CH2-OC(=O)-, CH3CH2CH2-OC(=O)-, (CH3)2CH-OC(=O)-, -S(=O)2-NH2 or -C(=O)-NH2, wherein R 3 Unsubstituted or replaced by 1, 2, 3 or 4 R 6 replaced.

[0171] Some of the implementation schemes are that each R 6 and -I, hydroxy, amino, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, methoxy, ethoxy, n-propyloxy, methylamino, ethylamino, or n-propylamino.

[0172] Some of the implementation schemes are that each R x are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C 1-4 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-C 1-3 Alkylene, cyclobutyl-C 1-3 Alkylene, cyclopentyl-C 1-3 Alkylene, cyclohexyl-C 1-3 Alkylene, phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C 1-3 Alkylene, naphthyl-C 1-3Alkylene, pyridyl-C 1-3 Alkylene, pyrimidinyl-C 1-3 Alkylene, furyl-C 1-3 Alkylene, thienyl-C 1-3 Alkylene, pyrrolyl-C 1-3 Alkylene, pyrazolyl-C 1-3 Alkylene, thiazolyl-C 1-3 Alkylene, oxazolyl-C 1-3 Alkylene, triazolyl-C 1-3 Alkylene, tetrazolyl-C 1-3 Alkylene, piperazinyl-C 1-3 Alkylene, piperidinyl-C 1-3 Alkylene, morpholinyl-C 1-3 Alkylene, thiomorpholinyl-C 1-3 Alkylene, tetrahydropyranyl-C 1-3 Alkylene, pyrrolidinyl-C 1-3 Alkylene, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-C(=O)- or C 1-3 Alkoxy-C(=O)-C 1-3 Alkylene.

[0173] Some of the implementation schemes are that each R y are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, C 1-4 Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-C 1-3 Alkylene, cyclobutyl-C 1-3 Alkylene, cyclopentyl-C 1-3 Alkylene, cyclohexyl-C 1-3 Alkylene, phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C 1-3 Alkylene, naphthyl-C 1-3 Alkylene, pyridyl-C 1-3 Alkylene, pyrimidinyl-C 1-3 Alkylene, furyl-C 1-3 Alkylene, thienyl-C 1-3 Alkylene, pyrrolyl-C 1-3 Alkylene, pyrazolyl-C 1-3 Alkylene, thiazolyl-C 1-3 Alkylene, oxazolyl-C 1-3 Alkylene, triazolyl-C 1-3 Alkylene, tetrazolyl-C 1-3 Alkylene, piperazinyl-C1-3 Alkylene, piperidinyl-C 1-3 Alkylene, morpholinyl-C 1-3 Alkylene, thiomorpholinyl-C 1-3 Alkylene, tetrahydropyranyl-C 1-3 Alkylene, pyrrolidinyl-C 1-3 Alkylene, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-C(=O)- or C 1-3 Alkoxy-C(=O)-C 1-3 Alkylene.

[0174] In some embodiments, G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein G is unsubstituted or replaced by 1, 2, 3 or 4 R 7 Replaced by; wherein, each R 7 has the meanings described in the present invention.

[0175] Some of the implementation schemes are that each R 7 are independently deuterium, -F, -Cl, -Br, -I, hydroxyl, amino, cyano, oxo, carboxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, -C(=O)-NR a R b 、-S(=O)2-NR a R b 、C 1-4 Alkyl-C(=O)-NH-, C 1-4 Alkyl-S(=O)2-NH-, C 1-4Alkoxy-C(=O)-NH-, CH3-C(=O)-, CH3CH2-C(=O)-, CH3CH2CH2-C(=O)-, (CH3)2CH-C(=O)-, CH3CH2CH2CH2- C(=O)-, CH3-S(=O)2-, CH3CH2-S(=O)2-, CH3CH2CH2-S(=O)2-, (CH3)2CH-S(=O)2-, CH3O-C(=O)-, CH3C H2O-C(=O)-、CH3CH2CH2O-C(=O)-、(CH3)2CHO-C(=O)-、CH3CH2CH2CH2O-C(=O)-、CH3-C(=O)-O-、CH3CH2-C(=O)-O-、CH3CH2CH2-C(=O)-O-、(CH3)2CH-C(=O)-O-、CH3CH2CH2CH2-C(=O)-O-、cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Among them, each R a and R b has the meanings described in the present invention.

[0176] Some of the implementation schemes are that each R a and R b are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, phenyl, naphthyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, phenyl-C 1-3 Alkylene, naphthyl-C 1-3 Alkylene, pyridyl-C 1-3 Alkylene, pyrimidinyl-C 1-3 Alkylene, furyl-C 1-3 Alkylene, thienyl-C 1-3 Alkylene, pyrrolyl-C 1-3 Alkylene, pyrazolyl-C 1-3 Alkylene, thiazolyl-C 1-3 Alkylene, oxazolyl-C 1-3 Alkylene, triazolyl-C 1-3 Alkylene, tetrazolyl-C 1-3 Alkylene, piperazinyl-C 1-3 Alkylene, piperidinyl-C 1-3 Alkylene, morpholinyl-C1-3 Alkylene, thiomorpholinyl-C 1-3 Alkylene, tetrahydropyranyl-C 1-3 Alkylene, pyrrolidinyl-C 1-3 Alkylene, C 1-3 Alkyl-S(=O)2- or C 1-3 Alkyl-C(=O)-; wherein each R a and R b are independently unsubstituted or substituted by 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo (=O), -C(=O)-NH2, C 1-3 Alkoxy C(=O)-, C 1-3 Alkyl-C(=O)-NH-, C 1-3 Alkyl-S(=O) t -NH-, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, methoxy, ethoxy, n-propyloxy, isopropyloxy, N-methylamino, N-ethylamino, N'N-dimethylamino, N'N-diethylamino or N'N-methylethylamino.

[0177] Some of the implementation schemes are that each R c are independently hydrogen, deuterium, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0178] In some embodiments, R is hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, -CH2F, -CHF2, -CF3, -CH2Cl or -CHCl2.

[0179] Some of the implementations are: 5a 、R 5b 、R 6a and R 6b Each is independently hydrogen, deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, -CH2F, -CHF2, -CF3, -CH2Cl or -CHCl2.

[0180] In some embodiments, the present invention includes but is in no way limited to compounds having one of the following structures or stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of compounds having one of the following structures:

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187] In some embodiments, the compounds of formula (I), (II), (III), (IV), (V), (VI) and (VII) of the present invention, and their pharmaceutically acceptable salts are 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 combinations thereof.

[0188] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) disclosed herein.

[0189] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, additive, adjuvant, vehicle or any combination thereof.

[0190] 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, pyramistol, cilomilast, indacaterol, olodaterol, mildestrol, qitongxun, salbutamol, carmoxicillin, budesonide, beclomethasone dipropionate , triamcinolone acetonide, flunisolide, mometasone furoate, roflenide, ciclesonide, ipratropium bromide, oxitropium bromide, tiotropium bromide, glycopyrrolate, umeclidinium bromide, vilanterol, aclidinium bromide, benralizumab, tralokinumab, revavatropate, crisaborole, fluocinolone acetonide, desoximetasone, mometasone, triamcinolone, betamethasone, alclometasone, desonide, hydrocortisone, clobetasol Clobatsol, halobetasol, diflorasone, meprobamate, tacrolimus, pimecrolimus, tazarotene, cyclosporine, apremilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, ibudilast, tofacitinib, JTE-052, baricitinib, upadacitinib, WBI-1001, MRX-6, GSK2981278, Durulucab, levitra, nimolizumab, troloxetine, etanercept, adalimumab, infliximab, ustekinumab, secukinumab, omalizumab, CIM-331, golimumab and pegylated thiabendazole, tocilizumab, calcipotriol, calcitriol, alitretinoin, VTP-38543, ZPL-389, aprepitant, tredipitant, foviprant, OC-459, SUN 13834, SB-011, VTP-43742, ARN6039, TAK-828, JTE-451, PF-04965842, PF-06651600, PF-06700841, PF-06650833, GR-MD-02, or any combination thereof.

[0191] On the other hand, the present invention relates to the use of the compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) disclosed in the present invention or its pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate diseases related to phosphodiesterase type 4 (PDE4).

[0192] In some embodiments, the disease associated with phosphodiesterase type 4 (PDE4) is a respiratory disease, allergy, inflammation, central nervous system disease, pulmonary fibrosis or non-insulin dependent diabetes mellitus.

[0193] 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;

[0194] The inflammation is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, allergic rhinitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis.

[0195] Another aspect of the present invention relates to methods for preparing, separating and purifying compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII).

[0196] Pharmaceutical compositions, formulations and administration of the compounds of the present invention

[0197] The present invention provides a pharmaceutical composition comprising a compound represented by Formula (I), (II), (III), (IV), (V), (VI), or (VII), or an individual 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, adsorbent, adjuvant, or vehicle, and optionally, other therapeutic and / or prophylactic ingredients.

[0198] Suitable carriers, excipients or adsorbents are well known to those skilled in the art and are described in detail in, for example, Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro AR et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

[0199] As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture, or vehicle that contributes to the consistency of a dosage form or pharmaceutical composition. Each excipient, when combined, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that could significantly reduce the efficacy of the disclosed compounds upon administration to a patient and interactions that could render the pharmaceutical composition unpharmaceutically acceptable. Furthermore, each excipient must be pharmaceutically acceptable, e.g., possess a sufficiently high degree of purity.

[0200] 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 function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to facilitate the production of a stable dosage form. Certain pharmaceutically acceptable excipients may be selected to facilitate the carrying or transport of the compound 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.

[0201] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth gum, 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, defoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents and filter aids. Those skilled in the art will recognize that certain pharmaceutically acceptable excipients can serve more than one function, and can 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 can be formulated using methods known in the art so as to provide quick, sustained, or delayed release of the active ingredient after administration to a patient.

[0202] The skilled artisan has the knowledge and skill to select a suitable pharmaceutically acceptable excipient in an appropriate amount for use in the present invention. In addition, there are a large number of resources available to the skilled artisan that describe pharmaceutically acceptable excipients and are useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0203] In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, various carriers for configuring pharmaceutically acceptable compositions and known techniques for their preparation are disclosed, and the respective contents of these documents are incorporated herein by reference. Except for any conventional carriers that are incompatible with the compounds of the present invention, such as those that may interact in a harmful manner with any other ingredient in the pharmaceutically acceptable compositions and produce any undesirable biological effects, it is contemplated that their use is within the scope of the present invention.

[0204] Suitable pharmaceutically acceptable carriers depend on the pharmaceutical form and are known to those skilled in the art.

[0205] 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.

[0206] Non-limiting examples of pharmaceutically acceptable carriers include those having components selected from the group consisting of lactose, gelatin, sugar alcohols (e.g., starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, colloidal silicon dioxide, carboxymethyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, buffered aqueous solutions, 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, for example an animal or plant phospholipid, a micellar agent, and an oil such as corn oil, or a mixture of two or more of the aforementioned components.

[0207] 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.

[0208] In one embodiment, the present invention relates to a pharmaceutical composition of the present invention, which forms a lipid-based drug delivery system (DDS) in an aqueous medium. The pharmaceutical composition, in addition to at least one compound of the compound represented by formula (I), (II), (III), (IV), (V), (VI) or (VII) or a salt thereof, further comprises at least one surfactant. Non-limiting examples of suitable surfactants are as described above. In various embodiments, the lipid-based drug delivery system forms the following structures: (1) liposomes (i.e., dispersed closed bilayer assemblies of lamellar phase in water); (2) nanoparticles of non-lamellar phase (e.g., cubic, hexagonal, sponge-like); or (3) micelles, emulsions, microemulsions (i.e., simple self-assembled structures of lipids and surfactants).

[0209] In some embodiments, the drug delivery system based on lipid that forms micelle, emulsion or microemulsion is preferred.The hydrophilic-lipophile balance value (HLB-value) of suitable surfactant or surfactant mixture that is used to form micelle, emulsion or microemulsion is generally about 8-18, about 10-18, or about 12-16.The 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, for example compound of formula (I) or its salt), at least one surfactant, optionally at least one cosolvent and optionally the mixture of at least one cosurfactant, ideally isotropic, under gentle stirring when being introduced into water, it spontaneously emulsifies and forms oil-in-water emulsifier.Gentle stirring can for example be provided by the motility of stomach.

[0210] The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0211] Thus, 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 combination thereof, the process comprising mixing the ingredients. Pharmaceutical compositions comprising a compound disclosed herein can be prepared, for example, by mixing at ambient temperature and atmospheric pressure.

[0212] 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.

[0213] Various solid oral dosage forms are used for the administration of the compounds of this invention, such as solid dosage forms of tablets, capsules, granules, lozenges and bulk powders. The compounds of this 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, solubilizing agents, buffers, adhesives, disintegrants, preservatives, coloring agents, flavorings, lubricants, etc. Timed-release capsules, tablets and gels are also advantageous for the administration of the compounds of this invention.

[0214] Various topical dosage forms can be used for the administration of the compounds of this 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, a transdermal patch. The compounds of this 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 delaying agents, disintegrating agents, emulsifiers, antioxidants, adhesives, bonding agents, tackifiers, solubilizing agents, dispersants, suspoemulsifiers, lubricants, hygroscopic agents, liposomes, microemulsions and beta-cyclodextrins, etc.

[0215] For the treatment of respiratory diseases, preferably the compounds of the invention are administered by inhalation.

[0216] Inhalable preparations include inhalable powders, metered aerosols containing propellants or inhalable preparations without propellants. For this purpose, they can be administered directly as powders (preferably in micronized form) or by spray solutions or suspensions containing them.

[0217] To the powdered compound of the invention may be added excipients or carriers which are generally non-toxic and chemically inert towards the compound of the invention, such as lactose or any other additive suitable for improving the respirable fraction.

[0218] Inhalation aerosols containing gaseous propellants such as hydrofluoroalkanes may contain the compound 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.

[0219] 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.

[0220] As used herein, the term "therapeutically effective amount" refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, the amount administered or allowed to reach equilibrium in the body is sufficient to treat, cure, or alleviate the symptoms of a disease. 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 route of administration, the clearance rate of the specific drug, the duration of treatment, combined medications, age, weight, sex, diet, and health of the patient. For a description of other factors that need to be considered in the art regarding a "therapeutically effective amount," see 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.

[0221] The dosage of the compounds of the invention depends on a variety of factors, including the specific disease being 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.

[0222] The amount of active ingredient that can be combined with the 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 topical administration to humans can conveniently contain from about 5 mg to about 250 mg / kg body weight / day of active agent, compounded with an appropriate and convenient amount of carrier material (which can comprise from 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.

[0223] Advantageously, they are administered in a dosage of 5-250 mg / kg body weight / day, preferably 25-150 mg / kg body weight / day.

[0224] The term "administration" refers to providing a therapeutically effective amount of a drug to an individual, and administration routes include oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. Dosage forms include ointments, lotions, tablets, capsules, pills, dispersible powders, granules, suppositories, pills, lozenges, injections, sterile solutions or non-aqueous solutions, suspensions, emulsions, patches, and the like. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (e.g., glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, dextran, and the like).

[0225] The preferred route of administration will vary depending on clinical circumstances, and dosage must be adjusted based on the patient being treated. The physician will determine the appropriate dosage for each individual patient. The therapeutically effective amount per unit dose depends on body weight, physiology, and the chosen vaccination regimen. The compound per unit dose refers to the weight of the compound per administration, excluding the weight of the vehicle (which is present in the drug).

[0226] Any suitable route of administration can be used to provide an effective dose of the compound of the present invention to a mammal, particularly a human. For example, oral administration, rectal administration, parenteral administration, topical administration, ophthalmic 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 represented by formula (I), (II), (III), (IV), (V), (VI), or (VII) is administered by inhalation or topical administration.

[0227] The pharmaceutical compositions provided herein can be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials, or syringes. The multiple dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as known and practiced in the art.

[0228] 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.

[0229] In some embodiments, the treatment methods of the present invention comprise 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 herein 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.

[0230] In some embodiments, the compounds of the present invention or pharmaceutical compositions comprising the compounds 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, the drug is administered once, twice, three times, or four times a day. In some embodiments, the drug is administered once a day. In yet other embodiments, the drug is administered twice a day. The drug can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosing regimen for the compounds of the present invention or pharmaceutical compositions comprising the compounds 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 for the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention, including the duration of implementation of the regimen, depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the technician. Such technicians should also understand that the appropriate dosing regimen may be required to adjust the individual patient's response to the dosing regimen, or when the individual patient's needs change over time.

[0231] The compounds of the present invention may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention may be administered separately with the other therapeutic agents via 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 patient's physical conditions, such as health, age, and weight. If formulated as a fixed dose, such a combination product utilizes the compounds of the present invention (within the dosage range described herein) and the other pharmaceutically active agent (within its dosage range).

[0232] Accordingly, in one aspect, the present invention encompasses 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.

[0233] The compound shown in formula (I), (II), (III), (IV), (V), (VI) or (VII) can be used to prevent, treat or alleviate the disease or symptom to which the compound shown in formula (I), (II), (III), (IV), (V), (VI) or (VII) is applicable. These other drugs can be administered simultaneously or successively with the compound shown in formula (I), (II), (III), (IV), (V), (VI) or (VII) by its commonly used approach and amount. When the compound shown in formula (I), (II), (III), (IV), (V), (VI) or (VII) is used simultaneously with one or more other drugs, the pharmaceutical unit dosage form containing the compound shown in this class of other drugs and formula (I), (II), (III), (IV), (V), (VI) or (VII) is preferred.

[0234] In various embodiments, the compounds described herein are combined with other drugs to provide combination therapies 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:

[0235] 2-agonists, such as albuterolamine, formoterol, salmeterol, and carmoxirol;

[0236] corticosteroids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, flunisolide, mometasone furoate, rofleponide, ciclesonide, fluocinolone acetonide, desoximetasone, mometasone, triamcinolone, betamethasone, alclomethasone, desonide, hydrocortisone, meprobamate;

[0237] anticholinergics or antimuscarinics, such as ipratropium, oxitropium, tiotropium, glycopyrrolate, or revatropate;

[0238] topical calcineurin inhibitors, such as tacrolimus, pimecrolimus, and cyclosporine;

[0239] Topical preparations of PDE4 inhibitors, such as apremilast, ibudilast, E-6005, OPA-15406, LEO-29102, DRM02, roflumilast, and cresabor;

[0240] Topical formulations of JAK kinase inhibitors, such as tofacitinib, JTE-052, baricitinib, and upadacitinib;

[0241] Topical nonsteroidal anti-inflammatory drugs, such as WBI-1001 and MRX-6;

[0242] Topical ROR agents, such as GSK2981278;

[0243] Injectable anti-IL4, IL-31, IL-22, IL-33, IL-12, IL-23, IL-17, IgE, IL-4 therapeutic drugs, such as Dupilumab, Levitra, Nemolizumab, Trakinumab, Etanercept, Adalimumab, Infliximab, Utekinumab, Secukinumab, Omazumilab, CIM-331;

[0244] Vitamin D analogs, such as calcipotriol and calcitriol;

[0245] Oral retinoic acid derivatives, such as alitretinoin;

[0246] Oral liver X receptor (LXR) selective agonists, such as VTP-38543;

[0247] Oral H4 receptor antagonists, such as ZPL-389;

[0248] Oral NK1 receptor antagonists, such as aprepitant and trodipitant;

[0249] Oral CRTH2 receptor antagonists, such as Fevipiprant and OC-459;

[0250] Oral chymotrypsin inhibitors, such as SUN 13834.

[0251] Preferably, the compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VII), alone or in combination with other active ingredients, are administered for the prevention and / or treatment of respiratory diseases or inflammatory skin diseases, such as chronic obstructive pulmonary disease (COPD), atopic dermatitis (AD) or psoriasis.

[0252] The treatment method comprising administering the compound or pharmaceutical composition of the present invention further comprises administering to the patient other anti-chronic obstructive pulmonary disease (COPD) or atopic dermatitis drugs (combination therapy), wherein the other anti-chronic obstructive pulmonary disease (COPD) or atopic dermatitis drugs are the drugs among the above-mentioned additional therapeutic agents or their combinations.

[0253] 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, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt or solvate thereof, in combination with 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, beta-2 adrenoceptor agonists, alpha-adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, bronchodilators, PDE inhibitors.

[0254] Uses of the compounds and pharmaceutical compositions of the present invention

[0255] The amount of the compound of the present invention or the compound in the composition of the present invention can be effective to detectably antagonize PDE4 to treat the following diseases: pain (e.g., acute pain, acute inflammatory pain, chronic inflammatory pain and neuropathic pain), acute inflammation, chronic inflammation, psoriatic arthritis, rheumatoid arthritis, psoriasis, proliferative and inflammatory skin diseases (e.g., atopic dermatitis, seborrheic dermatitis, contact dermatitis), asthma, chronic obstructive pulmonary disease (COPD), arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, 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, Sjogren's syndrome, systemic lupus erythematosus, the method comprising administering to the patient an effective amount of at least one compound represented by formula (I), (II) or (III) or a pharmaceutically acceptable salt or solvate thereof.

[0256] General synthetic steps

[0257] Generally, the compounds of the present invention can be prepared by the methods described herein, wherein, unless otherwise indicated, the substituents are as defined in Formula (I), (II), (III), (IV), (V), (VI), or (VII). The following reaction schemes and examples are provided to further illustrate the present invention.

[0258] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0259] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

[0260] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0261] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0262] Chromatographic columns used silica gel. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. H NMR spectra were measured at room temperature on a Bruker 400 MHz or 600 MHz NMR spectrometer using CDC13, DMSO-d6, CD3OD, or acetone-d6 as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0263] Low-resolution mass spectrometry (MS) data were determined using an Agilent 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min, mobile phase: 5%-95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid), UV detection at 210 / 254 nm, and electrospray ionization mode (ESI).

[0264] 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.

[0265] The stereo configuration of each chiral compound described in the present invention is resolved using one of the following analytical methods:

[0266] Analytical methods:

[0267] 1. Use an OD-H column (manufacturer: Daicel, specifications: 4.6×250 mm, 5 μm), mobile phase conditions: column temperature 30°C, flow rate 1 mL / min, 20% ethanol, 80% n-hexane;

[0268] 2. Use IA column (manufacturer: Daicel, specifications: 4.6×250 mm, 5 μm) with mobile phase conditions: column temperature 40°C, flow rate 1.0 mL / min, 40% ethanol, 60% n-hexane. The following abbreviations are used throughout this invention:

[0269]

[0270]

[0271] Synthesis scheme of compound (IA):

[0272]

[0273] Compound (IA) can be prepared by the above synthetic route, wherein R 1 、R 2 、R 3 ,X,X 1 、R 5a 、R 5b 、R 6a 、R 6b , R, n and G have the same meanings as those defined in the present invention. Compound (IA-1) is subjected to an esterification reaction with HOOC(CH2)nG under alkaline or acidic conditions to obtain compound (IA).

[0274] Synthesis scheme of compound (IB):

[0275]

[0276] Compound (IB) can be prepared by the above synthetic route, wherein R 1 、R 2 、R 3 ,X,X 1 、R 5a 、R 5b 、R 6a 、R 6b , R, n and G have the same meanings as those of the present invention. Compound (IB-1) or a salt thereof (such as hydrochloride, etc.) is subjected to a condensation reaction with HOOC(CH2)nG under appropriate conditions to obtain compound (IB).

[0277] Synthesis scheme of intermediate N and intermediate N':

[0278]

[0279] Intermediate N can be prepared by the synthesis method of intermediates, wherein, unless otherwise specified, R 1 and R 2 The starting material N1 reacts with the materials BnOH and diphenylphosphoryl azide under alkaline conditions to form an amino protecting group to obtain intermediate N2, intermediate N2 is subjected to catalytic hydrogenation reduction to obtain intermediate N3, intermediate N3 is subjected to diazotization reaction, and then undergoes substitution reaction with potassium iodide to obtain intermediate N; intermediate N is subjected to acidic conditions to remove the corresponding group R 1Intermediate N4 is obtained, and intermediate N4 undergoes substitution reaction with benzyl bromide to obtain intermediate N'.

[0280] Specific synthesis method of intermediate N and intermediate N':

[0281] The following specific synthesis methods of intermediates N and N' are merely examples of specific synthesis methods. The synthesis methods of intermediates N and N' referred to in the present invention should include, but are not limited to, the following specific examples.

[0282] Intermediate N2: Synthesis of benzyl (3-cyclopropylmethoxy-4-difluoromethoxy)phenyl)carbamate

[0283] 3-Cyclopropylmethoxy-4-difluoromethoxybenzoic acid (5.0 g, 19.4 mmol) was dissolved in toluene (25 ml), and DPPA (5.0 mL, 23.0 mmol) and triethylamine (4.3 mL, 31.0 mmol) were added. The mixture was reacted at room temperature for 1 h. Benzyl alcohol (3.0 mL, 29.0 mmol) was added, and the mixture was heated to 90°C for 3 h. The solvent was removed by concentration under reduced pressure, and the residue was added with water (100 ml). The mixture was then extracted with ethyl acetate (25 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 / 1) to obtain 5.01 g of a white solid in a 71% yield.

[0284] 1 H NMR (600MHz, CDCl3): δ (ppm) δ7.35-7.43 (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);

[0285] MS(ESI,pos.ion)m / z:364.10[M+H] + .

[0286] Intermediate N3: Synthesis of (3-cyclopropylmethoxy-4-difluoromethoxy)aniline

[0287] Dissolve benzyl (3-cyclopropylmethoxy-4-difluoromethoxy)phenyl)carbamate (145 mg, 0.45 mmol) in anhydrous methanol (6 mL). Add palladium on carbon (50 mg). Exclude air, introduce hydrogen, and react at room temperature for 2 h. Filter through celite to remove the catalyst. Concentrate the filtrate to yield 102 mg of a light red liquid (98% yield).

[0288] 1 H NMR (400MHz, CDCl3): δppm 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);

[0289] MS(ESI,pos.ion)m / z:230.10[M+H] + .

[0290] Synthesis of Intermediate N: 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene

[0291] 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), stirred well, and then cooled to below 0°C. Concentrated hydrochloric acid (17 mL) was added, and then cooled to -15°C. A solution prepared by sodium nitrite (5.3 g, 77.0 mmol) and water (15 mL) was added dropwise. The reaction was continued for 40 min. A solution prepared by potassium iodide (13.8 g, 83.1 mmol) and water (15 mL) was added. After the addition was complete, the temperature was raised to 0°C and the reaction was continued for 2 h. Water (200 mL) was added, stirred well, and the reaction was stopped. After returning to room temperature, the mixture was extracted with EA (200 mL×2). The organic phase was washed with saturated sodium sulfite, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 21 g of the target product as a light brown liquid with a yield of 96%.

[0292] 1 H NMR (400MHz, CDCl3) 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);

[0293] GC-MS: m / z 340.0.

[0294] Synthesis of Intermediate N4: 2-(difluoromethoxy)-5-iodophenol

[0295] The compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (4.9 g, 14.0 mmol) was dissolved in acetonitrile (8 mL), and water (10 mL) and concentrated hydrochloric acid (10 mL) were added. The reaction was carried out at 80°C for 4 h, and sodium hydroxide solution was added to adjust the pH to 5. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: PE / EA (v / v) = 5 / 1) to obtain 1.8 g of a light yellow liquid with a yield of 44%.

[0296] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.30 (s, 1H), 7.28 (d, J = 2.0Hz, 1H)), 7.15 (dd, J = 8.4, 2.0Hz, 1H), 7.02 (t, J F-H =74.7Hz,1H),6.90(d,J=8.4Hz,1H).

[0297] MS (ESI, pos.ion) m / z: 286.00 [M].

[0298] Synthesis of Intermediate N': 2-(Benzyloxy)-1-(Difluoromethoxy)-4-iodobenzene

[0299] The compound 2-(difluoromethoxy)-5-iodophenol (3.8 g, 13.0 mmol) and potassium carbonate (5.8 g, 42.0 mmol) were added to N,N-dimethylformamide (30 mL), and benzyl bromide (2.5 mL, 21.0 mmol) was added. The reaction was carried out at 100°C for 16 h. The solid was removed by filtration, and the filtrate was concentrated. Water (50 mL) was added and the mixture was extracted with EA (25 mL × 3). The organic phases were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: PE / EA (v / v) = 4 / 1) to obtain 4.8 g of a light yellow liquid with a yield of 96%.

[0300] 1 H NMR(400MHz, DMSO-d6)δ(ppm):7.57(d,J=1.9Hz,1H),7.45-7.47(m,2H),7.41(s,1H),7.39(d,J=3.4Hz,1H),7.33-7.37(m,2H),7.09(t,J F-H =74.2Hz,1H),7.00(d,J=8.4Hz,1H),5.18(s,2H).

[0301] Synthesis scheme of intermediate M:

[0302]

[0303]

[0304] Intermediate M can be prepared by the above two synthetic routes, wherein X is a halogen, R 1 、R 2 and R 3 has the meaning as described in the present invention.

[0305] The starting material M1 is subjected to enolization under alkaline conditions (such as lithium hydroxide, potassium hydroxide, etc.) and then a substitution reaction to obtain an intermediate M2. The intermediate M2 is subjected to a borylation reaction with diboronic acid pinacol ester under alkaline conditions to obtain a compound M3. M3 and intermediate N' (route 1) or intermediate N (route 2) are subjected to Suzuki coupling to obtain intermediates M4-1 and M4-6, respectively. Among them, route 1 is that the intermediate M4-1 is first subjected to a deprotection and salt-forming reaction to obtain an intermediate M4-2, and then under alkaline conditions (such as triethylamine, N,N-diisopropylethylamine, etc.) The substitution reaction obtains the intermediate M4-3, which is then subjected to catalytic hydrogenation reduction to obtain the intermediate M4-4, and finally a substitution reaction occurs under alkaline conditions to obtain the intermediate M4-5; while route 2 is that the intermediate M4-6 is first subjected to catalytic hydrogenation reduction under the action of palladium carbon to obtain the intermediate M4-7, which is then deprotected to obtain the intermediate M4-8, and finally a substitution reaction is carried out under alkaline conditions (such as triethylamine, N,N-diisopropylethylamine, etc.) to obtain the intermediate M4-9; M4-5 or M4-9 is then subjected to reduction reaction, halogenation reaction, azide reaction, hydrogenation reduction, etc. to finally obtain the intermediate M.

[0306] Specific synthesis method of intermediate M:

[0307] The synthesis method of intermediate M is merely an example of a specific synthesis method. The synthesis method of intermediate M referred to in the present invention should include, but is not limited to, the following specific examples. The intermediate M described in the present invention is not limited to a specific compound. Within the scope of the substituents described in the present invention, each specific example can optionally prepare the same or different intermediates M.

[0308] Intermediate M2: Synthesis of (R)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate

[0309] Compound (R)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (0.98 g, 4.0 mmol) was dissolved in dichloromethane (15 mL). DIPEA (3.4 mL, 20.5 mmol) and trifluoromethanesulfonic anhydride (1.3 mL, 7.7 mmol) were added at -15°C. After stirring for 10 min, the mixture was returned to room temperature and the reaction was continued for 18 h. The reaction was stopped and water (50 mL) was added. The mixture was extracted with dichloromethane (5 mL×3), dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 6 / 1) to obtain 1.3 g of a yellow oil with a yield of 86%.

[0310] 1 H NMR (400MHz, CDCl3) δ (ppm): 5.71 (dd, J=18.8, 1.6Hz, 1H), 4.99-5.06 (m, 1H), 4.24-4.41 (m, 2H), 3.76 (s, 3H), 1.42–1.47 (m, 9H).

[0311] MS-ESI: m / z 398.10[M+Na] + .

[0312] Intermediate M3: Synthesis of (R)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate

[0313] (R)-1-tert-Butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.3 g, 3.5 mmol), bipyraclostrobin (1.3 g, 5.1 mmol), KOAc (1.1 g, 11.2 mmol) and Pd(dppf)Cl2 (130 mg, 0.2 mmol) were added to dry 1,4-dioxane (30 mL). The reaction was carried out at 100°C for 13 h under nitrogen protection. The mixture was cooled to room temperature and filtered. Water (50 mL) was added to the filtrate, and the mixture was extracted with EtOAc (5 mL×3). The organic phases were dried over anhydrous sodium sulfate, the solvent was removed, and the mixture was concentrated. The mixture was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 6 / 1) to give 1.05 g of a light red liquid with a yield of 85%.

[0314] 1H NMR (400MHz, CDCl3) δ (ppm): 6.33 (dd, J = 23.4, 1.9Hz, 1H), 5.01-5.12 (m, 1H), 4.26-4.40 (m, 2H), 3.71–3.73 (m, 3H), 1.42–1.47 (m, 9H), 1.26 (s, 12H).

[0315] MS-ESI: m / z 376.15[M+Na] + .

[0316] Route 1:

[0317]

[0318] Compound 1-1: Synthesis of (R)-1-tert-butyl 2-methyl 4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate

[0319] (R)-1-tert-Butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (2.1 g, 5.9 mmol), 2-(benzyloxy)-1-(difluoromethoxy)-4-iodobenzene (5.8 g, 2.2 mmol), potassium phosphate (5.0 g, 24.0 mmol) and Pd(dppf)Cl2 (88 mg, The mixture was stirred for 2 h at 37 ℃ for 1 h. The reaction mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 3 h. The mixture was stirred for 4 h. The mixture was stirred for 5 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h.

[0320] 1 H NMR(400MHz, CDCl3)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).

[0321] MS-ESI: m / z 498.20[M+Na] + .

[0322] Compound 1-2: Synthesis of (R)-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride

[0323] Compound (R)-1-tert-butyl-2-methyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (2.3 g, 4.8 mmol) was dissolved in dichloromethane (5 mL), and a solution of HCl in ethyl acetate (4 mol / L, 15 mL) was added. The reaction was carried out at room temperature for 1 h, and the solvent was removed to obtain 2.02 g of a light yellow liquid with a yield of 100%.

[0324] 1 H NMR (400MHz, CD3OD) 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).

[0325] MS-ESI: m / z 376.05[M+H-HCl] + .

[0326] Compound 1-3: Synthesis of (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester

[0327] Compound (R)-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride (2.0 g, 4.9 mmol) was dissolved in dichloromethane (10 mL), and DIPEA (4.0 mL, 24 mmol) was added. After cooling to 0°C, acetyl chloride (1.1 g, 14 mmol) was added. The reaction was stopped after stirring at room temperature for 3 h. Water (20 mL × 3) was added and stirred, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous Na2SO4, concentrated, and separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 2) to obtain 1.8 g of a light yellow liquid with a yield of 89%.

[0328] 1H NMR (400MHz, CDCl3) 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).

[0329] MS-ESI: m / z 418.60[M+H] + .

[0330] Compound 1-4: Synthesis of (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidine-2-carboxylic acid methyl ester

[0331] Compound (R)-1-acetyl-4-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (4.5 g, 11 mmol) was dissolved in methanol (30 mL), 10% Pd / C (450 mg) was added, hydrogen was introduced, and the reaction was carried out at room temperature for 5 h. The mixture was filtered and the filtrate was concentrated to obtain 3.1 g of a light brown liquid with a yield of 87%.

[0332] 1 H NMR (400MHz, CDCl3) 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).

[0333] MS-ESI: m / z 330.00[M+H] + .

[0334] Compound 1-5: Synthesis of (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester

[0335] 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), and potassium carbonate (1.8 g, 13 mmol) and 2-iodopropane (1.5 g, 8.8 mmol) were added. The reaction was heated at 80°C for 4 h, and the solvent was removed under reduced pressure. Water (50 mL) was added, and the mixture was extracted with EtOAc (20 mL×3). The organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 1.5 g of a light brown liquid with a yield of 100%.

[0336] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.14 (d, J = 8.1 Hz, 1H), 6.87 (s, 1H), 6.83 (dd, J = 8.0, 1.9 Hz, 1H), 6.56 (t, J 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).

[0337] MS-ESI: m / z 372.30[M+H] + .

[0338] Compound 1-6: Synthesis of 1-((2R)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone

[0339] Compound (2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidine-2-carboxylic acid methyl ester (560 mg, 1.51 mmol) was dissolved in anhydrous THF (8 mL). Lithium borohydride (320 mg, 15.0 mmol) was added in an ice bath. The reaction was stopped after 1 h at room temperature. Saturated aqueous sodium chloride solution (20 mL) was added and extracted with EtOAc (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed to obtain 502 mg of a colorless liquid with a yield of 96%.

[0340] 1H NMR (400MHz, CD3OD) δ (ppm): 7.14 (d, J = 8.2 Hz, 1H), 6.85 (s, 1H), 6.81 (dd, J = 8.2, 1.8 Hz, 1H), 6.56 (t, J 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).

[0341] MS-ESI: m / z 344.10[M+H] + .

[0342] Compound 1-7: Synthesis of 1-((2R)-2-(bromomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone

[0343] The compound 1-((2R)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (493 mg, 1.44 mmol) was dissolved in EtOAc (20 mL), and triethylamine (442 mg, 4.37 mmol) was added. MsCl (333 mg, 2.91 mmol) was added in an ice bath, and the mixture was reacted at room temperature for 1 h. Lithium bromide (1.26 g, 14.56 mmol) was added, and the reaction was carried out at room temperature for 8 h. Water (30 mL) was added to stop the reaction, and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed to obtain 376 mg of a light yellow liquid with a yield of 64%.

[0344] 1 H NMR (400MHz, CD3OD): 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).

[0345] MS-ESI: m / z 408.15[M+H] + .

[0346] Compound 1-8: Synthesis of 1-((2R)-2-(azidomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone

[0347] 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), and sodium azide (512 mg, 7.9 mmol) was added. The reaction was heated at 80°C for 6 h, cooled to room temperature, and water (30 mL) was added. The mixture was extracted with EtOAc (10 mL×3). The organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 60 / 1) to obtain 223 mg of a light brown liquid with a yield of 76%.

[0348] 1 H NMR (400MHz, CDCl3) 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).

[0349] MS-ESI: m / z 369.20[M+H] + .

[0350] Compound 1-9: Synthesis of 1-((2R)-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone

[0351] 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), 10% Pd / C (23 mg) was added, hydrogen was introduced, and the reaction was carried out at room temperature for 3 h. The catalyst was removed by filtration, and the filtrate was concentrated to obtain 176 mg of a colorless liquid with a yield of 86%.

[0352] 1 H NMR (400MHz, CD3OD) 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).

[0353] MS-ESI: m / z 343.10[M+H] + .

[0354] Route 2:

[0355]

[0356] Compound 2-1: Synthesis of (R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate

[0357] (R)-1-tert-Butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.15 g, 3.3 mmol), 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (1.1 g, 3.2 mmol), potassium phosphate (2.1 g, 9.9 mmol) and Pd(dppf)Cl2(1 The product was dissolved in dry 1,4-dioxane (15 mL) and reacted at 100°C for 3 h under nitrogen. The reaction solution was filtered, and water (50 mL) was added to the filtrate, followed by extraction with EtOAc (5 mL × 3). The organic phases were dried over anhydrous sodium sulfate, and the solvent was removed. The concentrate was subjected to silica gel column chromatography (eluent: PE / EtOAc (v / v) = 8 / 1) to obtain 1.13 g of a light red liquid with a yield of 80%.

[0358] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.14 (d, J = 8.2 Hz, 1H), 6.90-6.97 (m, 2H), 6.63 (t, J F-H =75.4Hz,1H),6.00-6.03(m,1H),5.11-5.19(m,1H),4.47-4.66(m,2H),3.86-3.90(m,2H),3.7 6(d,J=4.0Hz,3H),1.46–1.52(m,9H),1.26-1.31(m,1H),0.61-0.70(m,2H),0.33-0.38(m,2H).

[0359] MS-ESI: m / z 462.20[M+Na] + .

[0360] Compound 2-2: Synthesis of (2R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

[0361] (R)-1-tert-Butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (1.1 g, 2.5 mmol) was dissolved in methanol (15 mL), Pd / C (260 mg) was added, hydrogen was introduced, and the reaction was carried out at room temperature for 7 h. The reaction solution was then filtered and the filtrate was concentrated to obtain 990 mg of a yellow liquid with a yield of 90%.

[0362] 1H NMR (400MHz, CDCl3) δ (ppm): 7.10 (d, J = 8.0 Hz, 1H), 6.77-6.81 (m, 2H), 6.60 (t, J F-H =74.2Hz,1H),4.30-4.40(m,1H),3.91-3.95(m,0.5H),4.02-4.06(m,0.5H),3.84-3.87(m,2H),3.76(d,J=6.7Hz,3H),3.30-3 .45(m,2H),2.62-2.68(m,1H),1.99-2.07(m,1H),1.43–1.47(m,9H),1.28-1.31(m,1H),0.62-0.67(m,2H),0.33-0.37(m,2H).

[0363] MS-ESI: m / z 464.25[M+Na] + .

[0364] Compound 2-3: Synthesis of (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride

[0365] Compound (2R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (990 mg, 2.2 mmol) was dissolved in dichloromethane (6 mL). HCl ethyl acetate solution (4 mol / L, 8 mL) was added. The mixture was stirred at room temperature for 50 min. The solvent was removed to obtain 751 mg of a white solid in a yield of 98%.

[0366] 1 H NMR (400MHz, CD3OD) δ (ppm): 7.14 (d, J = 8.2 Hz, 1H), 7.07 (s, 1H), 6.91-6.94 (m, 1H), 6.76 (t, J F-H =75.5Hz,2H),4.60-4.64(m,1H),3.94(d,J=6.9Hz,2H),3.90(s,3H),3.78-3.83(m,1H),3.65-3.72(m,1H),3.3 3-3.39(m,1H),2.82-2.89(m,1H),2.20-2.29(m,1H),1.28-1.36(m,1H),0.63-0.66(m,2H),0.37-0.41(m,2H).

[0367] MS-ESI:m / z 342.20[M+H-HCl] + .

[0368] Compound 2-4: Synthesis of (2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester

[0369] Compound (2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-2-carboxylic acid methyl ester hydrochloride (203 mg, 0.6 mmol) was dissolved in dichloromethane (5 mL), and DIPEA (0.2 mL, 1.0 mmol) and acetyl chloride (0.1 mL, 1.0 mmol) were added dropwise at 0°C. The reaction was stopped after stirring at room temperature for 5 h. The organic phase was washed with water (10 mL × 3) and dried over anhydrous Na2SO4. The concentrate was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to obtain 186 mg of a light yellow liquid with a yield of 82%.

[0370] 1 H NMR (400MHz, CD3OD) δ (ppm): 7.11 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.90-6.94 (m, 1H), 6.74 (t, J F-H =75.6Hz,1H),4.45-4.49(m,1H),4.08-4.12(m,1H),3.93(d,J=6.8Hz,2H),3.75(s,3H),3.50-3.64(m,2H), 2.67-2.74(m,1H),2.13(s,3H),1.99-2.06(m,1H),1.27-1.33(m,1H),0.62-0.67(m,2H),0.36-0.40(m,2H).

[0371] MS-ESI: m / z 384.20[M+H] + .

[0372] Compound 2-5: Synthesis of 1-((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone

[0373] 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. After reacting at room temperature for 4 h, ice water (15 mL) was added. After concentration, water (30 mL) was added and the mixture was extracted with EtOAc (20 mL × 3). The organic phase was washed with dilute hydrochloric acid (15 mL × 1, 1 M) and saturated aqueous sodium chloride solution (15 mL × 1). The organic phase was dried over anhydrous sodium sulfate. The solvent was removed to obtain 655 mg of a colorless liquid with a yield of 88%.

[0374] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.14 (d, J = 8.7 Hz, 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).

[0375] MS-ESI: m / z 356.25[M+H] + .

[0376] Compound 2-6: Synthesis of 1-((2R)-2-(bromomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0377] The compound 1-((2R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (520 mg, 1.46 mmol) was dissolved in EtOAc (20 mL), and triethylamine (525 mg, 5.19 mmol) was added. MsCl (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. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 146 mg of a light yellow liquid with a yield of 23%.

[0378] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.15 (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).

[0379] MS-ESI: m / z 419.15[M+H] + .

[0380] Compound 2-7: Synthesis of 1-((2R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0381] 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), and sodium azide (388 mg, 5.97 mmol) was added. The reaction was heated at 90°C for 2.5 h, cooled to room temperature, and water (30 mL) was added. The mixture was extracted with EtOAc (10 mL×3). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 60 / 1) to obtain 163 mg of a light brown liquid with a yield of 71%.

[0382] 1 H NMR (400MHz, CDCl3) 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).

[0383] MS-ESI: m / z 381.20[M+H] + .

[0384] Compound 2-8: Synthesis of 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0385] 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 EtOAc (10 mL × 3), and the organic phase was dried over anhydrous Na2SO4 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 a light brown liquid with a yield of 71%.

[0386] 1H NMR (400MHz, CD3OD) δ (ppm): 7.10 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 6.93–6.95 (m, 1H), 6.74 (t, J F-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).

[0387] MS-ESI: m / z 355.00[M+H] + . Example

[0388] Example 1: Methyl 3-((((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoate

[0389] Compound 1-((2R)-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (40 mg, 0.12 mmol), monomethyl isophthalate (27 mg, 0.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg, 0.59 mmol) and HOAT (30 mg, 0.22 mmol) were dissolved in distilled water. The product was added to chloromethane (5 mL) and cooled to 0°C. DIPEA (90 mg, 0.70 mmol) was added and the mixture was reacted at room temperature for 12 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 23 mg of a white viscous product with a yield of 39% and a purity of 92.31%.

[0390] 1H NMR (400MHz, CDCl3) δ (ppm): 8.94 (br.s, 1H), 8.59 (s, 1H), 8.17 (d, J = 7.6Hz, 1H), 8.07 (d, J = 7.7H z,1H),7.55(t,J=7.7Hz,1H),7.15(d,J=8.2Hz,1H),6.86(s,1H),6.83(d,J=8.3Hz,1H),6.57(t,J F-H =75.5Hz,1H),4.55–4.61(m,1H),4.37–4.43(m,1H),3.96–4.12(m,2H),3.96(s,3H),3.48(t,J=10.9 Hz,1H),3.25–3.39(m,2H),2.65–2.71(m,1H),2.20(s,3H),1.82–1.91(m,1H),1.38(d,J=5.9Hz,6H).

[0391] MS-ESI: m / z 505.15[M+H] + .

[0392] Example 2: 3-((((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoic acid

[0393]

[0394] The compound methyl 3-((((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoate (23 mg, 0.045 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL), and lithium hydroxide monohydrate (10 mg, 0.24 mmol) was added. The reaction was stopped at 50°C for 1.5 h, and dilute hydrochloric acid (1 M) was added to adjust the solution to pH = 1. THF was removed under reduced pressure, and the residue was extracted with EtOAc (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 18 mg of a light yellow solid with a yield of 80%.

[0395] 1 H NMR (400MHz, CD3OD): δ (ppm): 8.53 (s, 1H), 8.22 (d, J = 7.5Hz, 1H), 8.07 (d, J = 7.7Hz, 1H) ,7.62(t,J=7.8Hz,1H),7.08(d,J=8.2Hz,1H),6.99(s,1H),6.89–6.94(m,1H),6.66(t,J F-H=75.6Hz,1H),4.49–4.58(m,1H),4.36–4.44(m,1H),4.05–4.09(m,1H),3.72–3.90(m,2H),3.46(t,J=10 .9Hz,1H),3.32–3.41(m,1H),2.53–2.60(m,1H),2.17(s,3H),1.98–2.06(m,1H),1.26(d,J=6.0Hz,6H).

[0396] MS-ESI: m / z 491.30[M+H] + .

[0397] Example 3: N-(((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)-2-ethoxybenzamide

[0398]

[0399] Compound 1-((2R)-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (50 mg, 0.15 mmol), 2-ethoxybenzoic acid (37 mg, 0.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (142 mg, 0.74 mmol) and HOAT (40 mg, 0.29 mmol) were dissolved in dichloromethane. The product was added to methane (10 mL) and cooled to 0°C. DIPEA (116 mg, 0.90 mmol) was added and the mixture was reacted at room temperature for 6 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 30 mg of a white viscous product with a yield of 41% and a purity of 97.18%.

[0400] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.48 (br.s, 1H), 8.20 (d, J = 7.8Hz, 1H), 7.42–7.46 (m, 1H), 7.07–7.10(m,2H),6.98(d,J=8.2Hz,1H),6.81(s,1H),6.77(d,J=8.3Hz,1H),6.53(t,J F-H=75.6Hz,1H),4.41–4.48(m,1H),4.20–4.35(m,3H),3.95–4.03(m,1H),3.86–3.94(m,2H),3.39(t,J=10.7Hz,1H) ,3.17–3.26(m,1H),2.53–2.59(m,1H),2.14(s,3H),1.99–2.02(m,1H),1.52(t,J=6.9Hz,3H),1.27–1.31(m,6H).

[0401] MS-ESI: m / z 491.30[M+H] + .

[0402] Example 4: Methyl 4-((((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoate

[0403]

[0404] Compound 1-((2R)-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone (40 mg, 0.12 mmol), monomethyl terephthalate (27 mg, 0.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg, 0.59 mmol) and HOAT (30 mg, 0.22 mmol) were dissolved in distilled water. The product was dissolved in chloromethane (5 mL), cooled to 0°C, and DIPEA (90 mg, 0.70 mmol) was added. The mixture was reacted at room temperature for 12 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 26 mg of a white viscous product with a yield of 44% and a purity of 94.77%.

[0405] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.05 (br.s, 1H), 8.13 (d, J=8.4Hz, 2H), 7.97 (d, J= 8.4Hz,2H),7.16(d,J=8.1Hz,1H),6.86(s,1H),6.83(d,J=8.2Hz,1H),6.57(t,J F-H=75.4Hz,1H),4.55–4.61(m,1H),4.37–4.43(m,1H),3.97–4.13(m,2H),3.96(s,3H),3.48(t,J=10.9 Hz,1H),3.26–3.36(m,2H),2.64–2.72(m,1H),2.20(s,3H),1.81–1.89(m,1H),1.39(d,J=6.0Hz,6H).

[0406] MS-ESI: m / z 505.30[M+H] + .

[0407] Example 5: 4-((((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoic acid

[0408]

[0409] The compound methyl 4-((((2R)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoate (20 mg, 0.039 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL), and lithium hydroxide monohydrate (8 mg, 0.19 mmol) was added. The reaction was stopped at 50°C for 1.5 h, and dilute hydrochloric acid (1 M) was added to adjust the solution to pH = 1. Tetrahydrofuran was removed under reduced pressure, and the residue was extracted with EtOAc (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 15 mg of a light yellow solid with a yield of 77% and a purity of 91.92%.

[0410] 1 H NMR (400MHz, CD3OD) δ (ppm): 8.13 (d, J = 8.2Hz, 2H), 7.94 (d, J = 8.1Hz, 2H), 7.08 (d, J = 8.2Hz, 1H), 7.00 (s, 1H), 6.86–6.94 (m, 1H), 6.67 (t, J F-H =75.6Hz,1H),4.50–4.56(m,1H),4.36–4.44(m,1H),4.05–4.09(m,1H),3.70–3.88(m,2H),3.47(t,J=10 .9Hz,1H),3.32–3.40(m,1H),2.54–2.61(m,1H),2.18(s,3H),1.96–2.07(m,1H),1.27(d,J=6.0Hz,6H).

[0411] MS-ESI: m / z 491.05[M+H] + .

[0412] Example 6: Methyl 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoate

[0413]

[0414] Compound 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (60 mg, 0.17 mmol), monomethyl terephthalate (45 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg, 0.59 mmol) and HOAT (46 mg, 0.36 mmol) were dissolved in dichloromethane (5 mL) ), cooled to 0°C, added DIPEA (131 mg, 1.01 mmol), then returned to room temperature for 12 h, then added dichloromethane (15 mL), added water (10 mL), extracted with dichloromethane (10 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to give 58 mg of a white solid with a yield of 66% and a purity of 92.69%.

[0415] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.05 (br.s, 1H), 8.13 (d, J = 8.4Hz, 2H), 7.97 (d, J = 8.4Hz, 2H), 7.16 (d, J = 8.1Hz, 1H), 6.83 (s, 2H), 6.63 (t, J F-H =75.5Hz,1H),4.37–4.43(m,1H),3.97–4.04(m,2H),3.96(s,3H),3.90(d,J=6.9Hz,2H),3.48(t,J=10.9Hz,1H),3.25–3 .36(m,2H),2.65–2.71(m,1H),2.20(s,3H),1.81–1.90(m,1H),1.28–1.37(m,1H),0.66–0.71(m,2H),0.37–0.41(m,2H).

[0416] MS-ESI: m / z 517.30[M+H] + .

[0417] Example 7: 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoic acid

[0418]

[0419] The compound methyl 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoate (50 mg, 0.097 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL), and lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added. The reaction was stopped at 50° C. for 2 h, and dilute hydrochloric acid (1 M) was added to adjust the solution to pH = 1. THF was removed under reduced pressure, and the residue was extracted with EtOAc (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 48 mg of a white solid with a yield of 98% and a purity of 94.39%.

[0420] 1 H NMR(400MHz, CD3OD)δ(ppm):8.13(d,J=8.3Hz,2H),7.93(d,J=8.3Hz,2H),7.08(d,J=8.2Hz,1H),6.98(s,1H),6.89–6.91(m,1H),6.72(t,J F-H =75.6Hz,1H),4.36–4.43(m,1H),4.04–4.10(m,1H),3.82–3.88(m,1H),3.82(d,J=6.9Hz,2H),3.69–3.74(m,1H),3.48(t,J=10.8Hz, 1H),3.32–3.40(m,1H),2.54–2.61(m,1H),2.17(s,3H),1.96–2.05(m,1H),1.31–1.35(m,1H),0.59–0.63(m,2H),0.31–0.35(m,2H).

[0421] MS-ESI: m / z 503.20[M+H] + .

[0422] Example 8: N 1 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 4 -ethyl-N 4 -Methylterephthalamide

[0423]

[0424] Compound 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)benzoic acid (40 mg, 0.08 mmol), N-ethylmethylamine (14 mg, 0.24 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (76 mg, 0.40 mmol) and HOAT (21 mg, 0.15 mmol) were added. ) was dissolved in dichloromethane (5 mL), cooled to 0°C, and DIPEA (62 mg, 0.48 mmol) was added. The temperature was restored to room temperature and the reaction was continued for 12 h. Water (5 mL) was added and stirred. The mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 25 / 1) to obtain 16 mg of a white solid with a yield of 37% and a purity of 97.79%.

[0425] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.96 (br.s, 1H), 7.94 (d, J = 7.4Hz, 2H), 7.74 (d, J = 7.4Hz, 1H), 7.15 (d, J = 8.0Hz, 1H), 6.83 (s, 2H), 6.62 (t, J F-H =75.6Hz,1H),4.36–4.43(m,1H),3.94–4.03(m,2H),3.89(d,J=6.4Hz,2H ),3.55–3.65(m,1H),3.47(t,J=10.8Hz,1H),3.22–3.35(m,3H),3.09(s, 2H),2.92(s,1H),2.62–2.70(m,1H),2.18(s,3H),1.77–1.90(m,1H),1.2 2–1.35(m,1H),1.22–1.31(m,3H),0.65–0.70(m,2H),0.35–0.40(m,2H).

[0426] MS-ESI: m / z 544.40[M+H] + .

[0427] Example 9: Methyl 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate

[0428]

[0429] Compound 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (40 mg, 0.11 mmol), methyl 5-(methoxycarbonyl)-2-pyridinecarboxylate (30 mg, 0.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (108 mg, 0.56 mmol) and HOAT (30 mg, 0.22 mmol) were added. 1) was dissolved in dichloromethane (5 mL), cooled to 0°C, and DIPEA (87 mg, 0.67 mmol) was added. The temperature was returned to room temperature and the reaction was continued for 10 h. Dichloromethane (15 mL) was added, and the organic phase was washed with water (10 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 40 mg of a light yellow solid with a yield of 68% and a purity of 98.29%.

[0430] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.24 (s, 1H), 9.17 (br.s, 1H), 8.46 (d, J = 8.1Hz, 1H), 8.27 (d, J = 8.1Hz, 1H), 7.11 (d, J = 8.1Hz, 1H), 6.80 (s, 2H), 6.61 (t, J F-H =75.6Hz,1H),4.29–4.37(m,1H),3.92–4.08(m,2H),4.00(s,3H),3.84(d,J=6.9Hz,2H),3.60–3.67(m,1H),3.44(t,J=10.9Hz,1H ),3.23–3.32(m,1H),2.57–2.64(m,1H),2.18(s,3H),1.92–2.03(m,1H),1.27–1.34(m,1H),0.62–0.67(m,2H),0.31–0.38(m,2H).

[0431] MS-ESI: m / z 518.30[M+H] + .

[0432] Example 10: 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate hydrochloride

[0433]

[0434] The compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate (36 mg, 0.070 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL), and lithium hydroxide monohydrate (14 mg, 0.33 mmol) was added. The reaction was stopped at 50° C. for 2 h, and dilute hydrochloric acid (1 M) was added to adjust the solution to pH = 4. THF was removed under reduced pressure, and the residue was extracted with EtOAc (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 35 mg of a white solid with a yield of 97% and a purity of 97.13%.

[0435] 1 H NMR (400MHz, CD3OD) δ (ppm): 9.22 (s, 1H), 8.52 (dd, J = 8.1, 1.9Hz, 1H), 8.20 (d, J=8.1Hz,1H),7.06(d,J=8.2Hz,1H),6.98(s,1H),6.87–6.90(m,1H),6.71(t,J F-H =75.6Hz,1H),4.34–4.40(m,1H),4.02–4.06(m,1H),3.91–3.95(m,1H),3.82(d,J=6.9Hz,2H),3.69–3.74(m,1H),3.47(t,J=10.8Hz, 1H),3.32–3.39(m,1H),2.53–2.59(m,1H),2.17(s,3H),1.97–2.05(m,1H),1.30–1.34(m,1H),0.59–0.63(m,2H),0.32–0.35(m,2H).

[0436] MS-ESI: m / z 504.20 [M-HCl+H] + .

[0437] Example 11: N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Methylpyridine-2,5-dicarboxamide

[0438]

[0439] Compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate hydrochloride (30 mg, 0.06 mmol), N-ethylmethylamine (10 mg, 0.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (57 mg, 0.30 mmol) and HOAT (16 mg, 0. The product was dissolved in dichloromethane (5 mL) and cooled to 0°C. DIPEA (46 mg, 0.36 mmol) was added and reacted at room temperature for 6 h. Water (50 mL) was added and stirred, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 24 / 1) to give 18 mg of a white solid with a yield of 55% and a purity of 98.84%.

[0440] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.11 (s, 1H), 8.67 (s, 1H), 8.23 ​​(d, J = 7.9Hz, 1H), 7.89 (br.s, 1H), 7.11 (d, J = 7.9Hz, 1H), 6.81 (s, 2H), 6.60 (t, J F-H =75.6Hz,1H),4.26–4.36(m,1H),4.00–4.08(m,1H),3.92–3.96(m,1H),3. 86(d,J=6.8Hz,2H),3.59–3.67(m,2H),3.44(t,J=10.7Hz,1H),3.22–3.33 (m,2H),3.12(s,1.7H),2.97(s,1.3H),2.57–2.63(m,1H),2.18(s,3H),1. 92–2.01(m,1H),1.22–1.30(m,4H),0.63–0.69(m,2H),0.35–0.38(m,2H).

[0441] MS-ESI: m / z 545.30[M+H] + .

[0442] Example 12: Methyl 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)picolinate

[0443]

[0444] Compound 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (40 mg, 0.11 mmol), 2,6-pyridinedicarboxylic acid monomethyl ester (30 mg, 0.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (108 mg, 0.56 mmol) and HOAT (30 mg, 0.22 mmol) were dissolved in dichloromethane (5 mL). After cooling to 0°C, DIPEA (87 mg, 0.67 mmol) was added. The temperature was then returned to room temperature and the reaction was continued for 7 h. Dichloromethane (15 mL) was added and the organic phase was washed with water (10 The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 50 / 1) to obtain 34 mg of a light brown solid with a yield of 58% and a purity of 97.59%.

[0445] 1 H NMR (400 MHz, CDCl3) δ (ppm): 9.00 (br.s, 1H), 8.38 (d, J = 7.7 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.03 (tJ = 7.8 Hz, 1H), 7.09 (d, J = 8.7 Hz,1H),6.80(s,2H),6.60(t,J F-H =75.6 Hz,1H),4.33–4.40(m,1H),4.04(s,3H),4.00–4.04(m,1H),3.93–3.97(m,1H),3.82(d,J=6.9 Hz,2H),3.72–3.78(m,1H),3.48(t,J=10.8 Hz,1H),3.19–3.32(m,1H),2.54–2.61(m,1H),2.20(s,3H),1.96–2.05(m,1H),1.23–1.30(m,1H),0.63–0.67(m,2H),0.33–0.36(m,2H).

[0446] MS-ESI: m / z 518.20[M+H] + .

[0447] Example 13: 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))picolinic acid hydrochloride

[0448]

[0449] Compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)picolinic acid methyl ester (30 mg, 0.058 mmol) was dissolved in a mixed solvent of THF (6 mL) and water (3 mL). Lithium hydroxide monohydrate (12 mg, 0.29 mmol) was added, and the mixture was reacted at 50°C for 1 h. The mixture was cooled to room temperature, and dilute hydrochloric acid (1 M) was added to adjust the pH of the solution to 4. The THF was removed under reduced pressure, and the residue was extracted with EtOAc (10 mL×2). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 29 mg of a white solid with a yield of 92% and a purity of 97.01%.

[0450] 1 H NMR (400 MHz, CD3OD) δ (ppm): 8.35 (d, J = 7.4 Hz, 2H), 8.19–8.23 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.94 (s, 1H), 6.85–6.88 (m, 1H), 6.69 (t, J F-H =75.7 Hz,1H),4.38–4.45(m,1H),4.01–4.05(m,1H),3.83–3.95(m,2H),3.79(d,J=6.8 Hz,2H),3.44(t,J=10.8Hz,1H),3.32–3.39(m,1H),2.52–2.59(m,1H),2.29(s,0.5H),2. 17(s,2.5H),2.01–2.09(m,1H),1.20–1.26(m,1H),0.59–0.62(m,2H),0.30–0.35(m,2H).

[0451] MS-ESI: m / z 504.20[M+H] + .

[0452] Example 14: N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 6 -ethyl-N 6 -Methylpyridine-2,6-dicarboxamide

[0453]

[0454] Compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))picolinic acid hydrochloride (30 mg, 0.06 mmol) was dissolved in dry THF (4 mL), CDI (39 mg, 0.24 mmol) was added, and the reaction was carried out at 60°C for 1 h. N-ethylmethylamine (14 mg, 0.24 mmol) was added, and the reaction was continued for 6 h. Water (15 mL) was added and stirred, and the mixture was extracted with EtOAc (5 mL×3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to obtain 14 mg of a light yellow solid with a yield of 43% and a purity of 98.99%.

[0455] 1 H NMR(400MHz, CDCl3)δ(ppm):8.22–8.25(m,1H),7.95–7.99(m,1H),7.71–7.79(m,1H),7.09–7.12(m,1H),6.79(s,2H),6.60(t,J F-H =75.6Hz,1H),4.27–4.35(m,1H),3.90–4.03(m,2H),3.83–3.86(m,2H),3 .62–3.72(m,2H),3.35–3.44(m,2H),3.20–3.30(m,1H),3.16(s,1.5H),3 .011(s,1.5H),2.52–2.60(m,1H),2.14(s,3H),1.94–2.05(m,1H),1.20( t,J=7.1Hz,3H),1.13–1.17(m,1H),0.62–0.67(m,2H),0.33–0.38(m,2H).

[0456] MS-ESI: m / z 545.20[M+H] + .

[0457] Example 15: N-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-2-ethoxybenzamide

[0458]

[0459] 2-Ethoxybenzoic acid (46 mg, 0.28 mmol) was dissolved in dry tetrahydrofuran (4 mL), and CDI (49 mg, 0.30 mmol) was added. The mixture was reacted at room temperature for 1 h. 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (60 mg, 0.17 mmol) was added and the mixture was reacted at 60°C for 6 h. The mixture was cooled to room temperature, and water (15 mL) was added. The organic phase was extracted with EtOAc (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to give 35 mg of a light brown solid with a yield of 41% and a purity of 94.40%.

[0460] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.60 (br.s, 1H), 7.38 (t, J = 7.7Hz, 1H), 7.09 (d, J = 7.1Hz, 1H), 7.02(t,J=7.3Hz,1H),6.93(d,J=8.2Hz,1H),6.74(s,1H),6.73(d,J=8.4Hz,1H),6.59(t,J F-H =75.6Hz,1H),4.50–4.54(m,1H),4.10–4.14(m,2H),3.84–3.90(m,1H) ,3.85(d,J=6.9Hz,2H),3.56–3.65(m,1H),3.34–3.47(m,2H),3.15–3. 23(m,1H),2.63–2.70(m,1H),2.03(s,3H),1.81–1.87(m,1H),1.43(t, J=6.9Hz,3H),1.29–1.36(m,1H),0.65–0.68(m,2H),0.35–0.37(m,2H).

[0461] MS-ESI: m / z 503.25[M+H] + .

[0462] Example 16: N-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-2-ethoxy-3-fluorobenzamide

[0463]

[0464] Compound 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (50 mg, 0.14 mmol), 2-ethoxy-3-fluorobenzoic acid (41 mg, 0.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and HOAT (29 mg, 0.21 mmol) were dissolved in distilled water. The product was dissolved in chloromethane (10 mL), cooled to 0°C, and DIPEA (85 mg, 0.66 mmol) was added. After returning to room temperature, the reaction was continued for 8 h. Dichloromethane (15 mL) was added, and the organic phase was washed with water (20 mL × 2), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to obtain 53 mg of a light brown solid with a yield of 72% and a purity of 93.25%.

[0465] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.64 (br.s, 1H), 7.08–7.18 (m, 4H), 6.73–6.78 (m, 2H), 6.59 (t, J F-H =75.6Hz,1H),4.48–4.55(m,1H),4.17–4.32(m,2H),3.82–3.91(m,1H) ,3.86(d,J=6.9Hz,2H),3.53–3.64(m,1H),3.37–3.47(m,2H),3.15–3. 25(m,1H),2.65–2.70(m,1H),2.03(s,3H),1.81–1.94(m,1H),1.37(t, J=6.9Hz,3H),1.29–1.36(m,1H),0.64–0.69(m,2H),0.35–0.38(m,2H).

[0466] MS-ESI: m / z 521.30[M+H] + .

[0467] Example 17: N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -isopropyl-N 5 -Methylpyridine-2,5-dicarboxamide

[0468]

[0469] Compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate hydrochloride (60 mg, 0.12 mmol), N-isopropylmethylamine (43 mg, 0.59 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.59 mmol) and HOAT (32 mg, The product was dissolved in dichloromethane (5 mL) and cooled to 0°C. DIPEA (77 mg, 0.60 mmol) was added and reacted at room temperature for 12 h. Water (30 mL) was added and the product was extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated. The product was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 66 / 1) to give 42 mg of a white solid with a yield of 63% and a purity of 98.25%.

[0470] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.10 (br.s, 1H), 8.62 (s, 1H), 8.21 (d, J = 7.9Hz, 1H), 7. 80–7.87(m,1H),7.09(d,J=7.9Hz,1H),6.79(s,1H),6.76(d,J=8.2Hz,1H),6.58(t,J F-H =75.6Hz,1H),4.88–5.00(m,0.4H),4.26–4.33(m,1H),3.97–4.06(m,1H),3.90–3.94(m,1 H),3.80–3.87(m,0.6H),3.84(d,J=6.8Hz,2H),3.55–3.65(m,1H),3.42(t,J=10.8Hz,1H) ,3.20–3.29(m,1H),2.97(s,1.8H),2.79(s,1.2H),2.53–2.61(m,1H),2.16(s,3H),1.90– 2.02(m,1H),1.27–1.34(m,1H),1.16–1.24(m,6H),0.62–0.66(m,2H),0.33–0.36(m,2H).

[0471] MS-ESI: m / z 559.20[M+H] + .

[0472] Example 18: N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -(4-Fluorophenyl)-N5 -Methylpyridine-2,5-dicarboxamide

[0473]

[0474] Compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate hydrochloride (60 mg, 0.12 mmol), 4-fluoro-N-methylaniline (74 mg, 0.59 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.59 mmol) and HOAT (32 mg) were added. , 0.24 mmol) was dissolved in dichloromethane (5 mL), cooled to 0°C, and DIPEA (78 mg, 0.60 mmol) was added. The mixture was reacted at room temperature for 12 h, and water (30 mL) was added. The mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: EtOAc (v) = 100%) to obtain 48 mg of a white solid with a yield of 66% and a purity of 96.39%.

[0475] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.99 (br.s, 1H), 8.50 (s, 1H), 7.99 (d, J = 7.8Hz, 1H), 7. 68(d,J=7.4Hz,1H),6.92–7.09(m,5H),6.77(s,1H),6.76(d,J=8.2Hz,1H),6.58(t,J F-H =75.6Hz,1H),4.20–4.27(m,1H),3.86–3.99(m,2H),3.83(d,J=6.8Hz,2H),3.49–3.56(m,1H),3.48(s,3H),3.38(t,J=10.7Hz,1H ),3.17–3.27(m,1H),2.51–2.58(m,1H),2.13(s,3H),1.86–1.94(m,1H),1.23–1.32(m,1H),0.60–0.65(m,2H),0.32–0.35(m,2H).

[0476] MS-ESI: m / z 611.15[M+H] + .

[0477] Example 19: N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5-(2-(dimethylamino)ethyl)-N 5 -Methylpyridine-2,5-dicarboxamide

[0478]

[0479] Compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate hydrochloride (60 mg, 0.12 mmol), N 1 ,N 1 ,N 2 1-Trimethylethylenediamine (60 mg, 0.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.59 mmol) and HOAT (32 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL). After cooling to 0°C, DIPEA (77 mg, 0.60 mmol) was added and the mixture was reacted at room temperature for 12 h. Water (30 mL) was added and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 18 / 1) to give 42 mg of a white solid with a yield of 60% and a purity of 97.07%.

[0480] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.08 (br.s, 1H), 8.67 (s, 1H), 8.20 (d, J = 8.0Hz, 1H), 7. 87–7.94(m,1H),7.09(d,J=8.0Hz,1H),6.78(s,1H),6.77(d,J=5.4Hz,1H),6.58(t,J F-H =73.2Hz,1H),4.26–4.34(m,1H),3.98–4.04(m,1H),3.89–3.93(m,1H),3.84(d,J=6.9H z,2H),3.66–3.74(m,1H),3.57–3.65(m,1H),3.41(t,J=10.8Hz,1H),3.19–3.34(m,2H) ,3.01–3.10(m,3H),2.61–2.70(m,1H),2.54–2.61(m,1H),2.37(s,3H),2.15(s,3H),1. 90–2.07(m,2H),2.04(s,3H),1.23–1.34(m,1H),0.61–0.66(m,2H),0.32–0.36(m,2H).

[0481] MS-ESI: m / z 588.50[M+H] + .

[0482] Example 20: N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -methyl-N 5 -(2,2,2-trifluoroethyl)pyridine-2,5-dicarboxamide

[0483]

[0484] Compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate hydrochloride (60 mg, 0.12 mmol), N-methyl-2,2,2-trifluoroethylamine hydrochloride (71 mg, 0.47 mmol) and HOAT (33 mg, 0.24 mmol) were dissolved in dichloromethane (10 mL), and 1-ethyl-3-(3-difluoromethoxy)phenyl was added in an ice bath. Methylaminopropyl)carbodiimide hydrochloride (115 mg, 0.60 mmol) and DIPEA (142 mg, 1.10 mmol) were reacted at room temperature for 4 h, water (30 mL) was added, and the aqueous phase was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 54 / 1) to obtain 32 mg of a white solid with a yield of 44% and a purity of 97.31%.

[0485] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.66 (br.s, 1H), 7.91 (s, 2H), 7.33 (s, 1H), 7.09 (d, J = 8.2Hz, 1H), 6.75 (d, J = 7.4Hz, 1H), 6.76 (s, 1H), 6.58 (t, J F-H =75.6Hz,1H),4.49–4.53(m,1H),4.16–4.29(m,1H),4.02–4.05(m,2H) ,3.84–3.91(m,1H),3.85(d,J=6.8Hz,2H),3.72(t,J=11.6Hz,1H),3.43 –3.49(m,1H),3.10–3.23(m,4H),2.57–2.63(m,1H),2.01(s,3H),1.86 –1.95(m,1H),1.25–1.36(m,1H),0.62–0.66(m,2H),0.33–0.37(m,2H).

[0486] MS(ESI,pos.ion)m / z:599.10[M+H] + .

[0487] Example 21: N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -(cyanomethyl)-N 5 -Methylpyridine-2,5-dicarboxamide

[0488]

[0489] Compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate hydrochloride (80 mg, 0.16 mmol), 2-(methylamino)acetonitrile hydrochloride (71 mg, 0.84 mmol) and HOAT (43 mg, 0.32 mmol) were dissolved in dichloromethane (10 mL), and 1-ethyl-3-(3-dimethylaminopropyl)propane was added in an ice bath. To the mixture of 4-[(2-[(2-amino-3-methyl)-1-carbodiimide)] hydrochloride (155 mg, 0.81 mmol) and DIPEA (186 mg, 1.44 mmol) were reacted at room temperature for 15 h. Water (30 mL) was added, and the aqueous phase was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 54 / 1) to give 18 mg of a white solid with a yield of 20% and a purity of 93.44%.

[0490] MS(ESI,pos.ion)m / z:556.40[M+H] + .

[0491] Example 22: N 2 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -(2-amino-2-oxoethyl)-N 5 -Methylpyridine-2,5-dicarboxamide

[0492]

[0493] Compound 6-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl))nicotinate hydrochloride (60 mg, 0.12 mmol), 2-(methylamino)acetamide hydrochloride (50 mg, 0.40 mmol) and HOAT (33 mg, 0.24 mmol) were dissolved in dichloromethane (10 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbonyl was added in an ice bath. Diimine hydrochloride (115 mg, 0.60 mmol) and DIPEA (146 mg, 1.13 mmol) were reacted at room temperature for 3 h. After cooling to room temperature, water (30 mL) was added and stirred. The aqueous phase was extracted with dichloromethane (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to give 34 mg of a white solid with a yield of 49% and a purity of 93.49%.

[0494] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.16 (br.s, 1H), 8.74 (s, 1H), 8.24 (d, J = 7.5Hz, 1H), 7.96 (d,J=7.4Hz,1H),7.09(d,J=8.0Hz,1H),6.79(s,1H),6.77(d,J=3.9Hz,1H),6.59(t,J F-H =75.6Hz,1H),4.25–4.34(m,1H),4.15–4.24(m,1H),3.90–3.94(m,1H),3. 84(d,J=6.9Hz,2H),3.55–3.62(m,1H),3.42(t,J=10.8Hz,1H),3.22–3.29 (m,1H),3.11(m,3H),2.55–2.62(m,1H),2.15(s,3H),1.89–1.98(m,1H),1 .62–1.67(m,2H),1.25–1.33(m,1H),0.62–0.66(m,2H),0.32–0.36(m,2H).

[0495] MS(ESI,pos.ion)m / z:574.05[M+H] + .

[0496] Example 23: 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-o-methoxybenzamide

[0497]

[0498] Step 1: Synthesis of methyl o-anisole

[0499] To the compound methyl salicylate (1.02 g, 6.68 mmol) was added anhydrous DMF (10 mL), and the mixture was stirred at room temperature until completely dissolved. Potassium carbonate (2.79 g, 19.98 mmol) and iodomethane (2.86 g, 20.1 mmol) were then added, and the mixture was heated to 60°C and stirred for 2 h. The reaction was stopped and concentrated. Water (15 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The mixture was dried over anhydrous Na2SO4, concentrated, and separated by silica gel column chromatography (eluent PE / EtOAc (v / v) = 19:1) to give 1.12 g of a yellow oil with a yield of 100.51%.

[0500] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.84-7.78 (m, 1H), 7.52-7.46 (m, 1H), 7.03-6.96 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H).

[0501] MS-ESI: m / z 167.20[M+H] + .

[0502] Step 2: Synthesis of o-Anisic Acid

[0503] THF (12 mL) and water (10 mL) were added to methyl o-anisate (1.11 g, 6.68 mmol), and lithium hydroxide monohydrate (0.86 g, 20.45 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 h to stop the reaction. Dilute hydrochloric acid (1 M) was added under an ice bath to adjust the pH to 5-6. The mixture was concentrated, and water (10 mL) was added. The mixture was extracted with EtOAc (15 mL × 3), dried over anhydrous Na2SO4, concentrated, and separated by silica gel column chromatography (gradient elution, eluent DCM / MeOH (v / v) = 1 / 0 to 19 / 1 to 18 / 1 to 17 / 1) to give 153.6 mg of a light cyan solid with a yield of 15.12%.

[0504] 1 H-NMR (400MHz, CD3OD) δ (ppm): 7.89-7.82 (m, 1H), 7.60-7.52 (m, 1H), 7.16 (d, J = 8.1Hz, 1H), 7.04 (t, J = 8.1Hz, 1H), 3.93 (s, 3H).

[0505] MS-ESI: m / z 153.20[M+H] + .

[0506] Step 3: Synthesis of 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)-o-methoxybenzamide

[0507] To o-anisic acid (73.9 mg, 0.49 mmol) was added anhydrous THF (8 mL), and the mixture was stirred at room temperature until dissolved. Carbonyldiimidazole (86.5 mg, 0.52 mmol) was added and stirred at room temperature for 1 h. 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (93.2 mg, 0.26 mmol) was then added. The mixture was heated to 60°C and stirred for 5 h to stop the reaction. The mixture was concentrated, and water (15 mL) was added. The mixture was extracted with EtOAc (30 mL×3), dried over anhydrous Na2SO4, concentrated, and separated by silica gel column chromatography (eluent PE / EtOAc (v / v) = 1:3) to give 91.1 mg of a light brown oil with a yield of 70.9% and a purity of 91.93%.

[0508] 1 H-NMR(400MHz, CDCl3)δ(ppm):8.24-8.14(m,1H),7.53-7.42(m,1H),7.12(s,4H),7.05–6.96(m,1H),6.60(t,J F-H =75.5Hz,1H),4.00(s,3H),3.98–3.87(m,3H),3.86-3.76(m,3H),3.46-3.34(m,1H),2. 16(s,2H),2.12–1.96(m,2H),1.38–1.18(m,4H),0.70–0.55(m,2H),0.40–0.28(m,2H).

[0509] MS-ESI: m / z 489.25[M+H] + .

[0510] Example 24: 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)o-methylaminobenzamide

[0511]

[0512] Step 1: Synthesis of methyl o-aminobenzoate

[0513] Anhydrous DMF (10 mL) was added to methyl anthranilate (1.03 g, 6.81 mmol). The mixture was stirred at room temperature until completely dissolved, followed by the addition of potassium carbonate (2.94 g, 21.08 mmol) and iodomethane (0.87 g, 6.1 mmol). The mixture was heated to 60°C and stirred for 6 h. The reaction was stopped and concentrated. Water (15 mL) was added, and the mixture was extracted with EtOAc (20 mL × 3). The mixture was dried over anhydrous Na2SO4, concentrated, and separated by silica gel column chromatography (eluent PE) to obtain 483 mg of a bright yellow oil with a yield of 43%.

[0514] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.96-7.88 (m, 1H), 7.45-7.35 (m, 1H), 6.72-6.56 (m, 2H), 3.87 (s, 3H), 2.98-2.87 (m, 3H).

[0515] MS-ESI: m / z 166.25[M+H] + .

[0516] Step 2: Synthesis of o-aminobenzoic acid

[0517] To methyl o-aminobenzoate (247.1 mg, 1.50 mmol) was added THF (4 mL) and water (4 mL), followed by potassium hydroxide (142 mg, 2.53 mmol). The mixture was heated to 60°C and stirred for 22 h to stop the reaction. Dilute hydrochloric acid (1 M) was added under ice bath to adjust the pH to 2-3. The mixture was concentrated, and water (10 mL) was added. The mixture was extracted with EtOAc (15 mL × 3), dried over anhydrous Na2SO4, and concentrated to give 213.1 mg of a white solid with a yield of 94.24%.

[0518] 1 H-NMR (400MHz, CD3OD) δ (ppm): 7.94-7.82 (m, 1H), 7.45-7.32 (m, 1H), 6.77-6.66 (m, 1H), 6.62-6.51 (m, 1H), 2.90 (s, 3H).

[0519] MS-ESI: m / z 152.20[M+H] + .

[0520] Step 3: Synthesis of 4-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)amino)o-methylaminobenzamide

[0521] To o-aminobenzoic acid (72.1 mg, 0.48 mmol) was added anhydrous THF (8 mL), and the mixture was stirred at room temperature until completely dissolved. Carbonyldiimidazole (86.9 mg, 0.53 mmol) was added and stirred at room temperature for 2 h. 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (106.6 mg, 0.30 mmol) was then added. The mixture was heated to 60°C and stirred for 6 h. The reaction was stopped and concentrated. Water (15 mL) was added, and the mixture was extracted with EtOAc (30 mL×3). The mixture was dried over anhydrous Na2SO4, concentrated, and separated by silica gel column chromatography (eluent PE:EtOAc (v / v) = 1:3) to give 59.3 mg of a light brown oil with a yield of 40.4%.

[0522] 1 H-NMR(400MHz, CDCl3)δ(ppm):7.54-7.48(m,1H),7.37–7.30(m,1H),7.17–7.12(m,1H),6.85–6.80(m,2H),6.69–6.64(m,2H),6.63(t,J F-H =75.5Hz,1H),4.42–4.32(m,1H),4.00–3.92(m,2H),3.90–3.86(m,2H),3.50–3.40(m,1H),3.38–3.22(m,2H),2.88( s,3H),2.70–2.60(m,1H),2.18(s,3H),2.08–1.98(m,2H),0.95–0.85(m,2H),0.72–0.64(m,2H),0.43–0.34(m,2H).

[0523] MS-ESI: m / z 488.25[M+H] + .

[0524] Example 25: 1-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)piperidine-4-carboxylic acid

[0525]

[0526] Step 1: Methyl 1-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)piperidine-4-carboxylate

[0527] The compound 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (100 mg, 0.28 mmol) was dissolved in dry tetrahydrofuran (10 mL), and DIPEA (44 mg, 0.34 mmol) and 4-nitrophenyl chloroformate (62 mg, 0.31 mmol) were added. The reaction was carried out at room temperature for 1.5 h. Methyl piperidine-4-carboxylate (47 mg, 0.32 mmol) was added, and the reaction was carried out at room temperature for 14 h. Water (10 mL) was added, and the mixture was extracted with EtOAc (5 mL×3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to give 132 mg of a white solid with a yield of 49%.

[0528] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.14 (d, J = 8.7Hz, 1H), 7.10 (d, J = 5.6Hz, 1H), 6.81 (s, 2H), 6.62 (t, J F-H =75.5Hz,1H),4.24–4.30(m,1H),3.91–3.99(m,3H),3.89(d,J=7.0Hz,2H),3.7 0–3.75(m,1H),3.70(s,3H),3.42(t,J=11.0Hz,1H),3.13–3.28(m,2H),2.85–2 .92(m,2H),2.58–2.64(m,1H),2.46–2.51(m,1H),2.15(s,3H),1.92–1.94(m,2 H),1.66–1.81(m,3H),1.26–1.34(m,1H),0.65–0.70(m,2H),0.37–0.40(m,2H).

[0529] MS(ESI,pos.ion)m / z:524.20[M+H] + .

[0530] Step 2: 1-((((2R)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)piperidine-4-carboxylic acid

[0531] The compound 1-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)piperidine-4-carboxylic acid methyl ester (130 mg, 0.25 mmol) was dissolved in a mixed solvent of THF (3 mL) and water (2 mL), and lithium hydroxide monohydrate (52 mg, 1.24 mmol) was added. The reaction was stopped at 50°C for 1.5 h, and dilute hydrochloric acid (1 M) was added to adjust the solution to pH = 1. The THF was removed under reduced pressure, and the residue was extracted with dichloromethane (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 126 mg of a white solid with a yield of 99% and a purity of 96.66%.

[0532] 1 H NMR (400MHz, CD3OD) δ (ppm): 7.11 (d, J = 8.2 Hz, 1H), 7.02–7.03 (m, 1H), 6.90–6.92 (m, 1H), 6.74 (t, J F-H =75.7Hz,1H),4.59–4.68(m,2H),4.22–4.29(m,1H),4.02–4.06(m,1H),3.93–3 .98(m,2H),3.93(d,J=6.8Hz,2H),3.54–3.59(m,1H),3.41–3.48(m,1H),2.92– 2.98(m,2H),2.48–2.64(m,2H),2.21(s,0.8H),2.15(s,2.2H),1.89–1.94(m,3 H),1.54–1.63(m,2H),1.29–1.37(m,1H),0.63–0.67(m,2H),0.37–0.41(m,2H).

[0533] MS-ESI: m / z 510.20[M+H] + .

[0534] Example 26: N 1 -(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 4 -ethyl-N 4 -Methylpiperidine-1,4-dicarboxamide

[0535]

[0536] Compound 1-((((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)piperidine-4-carboxylic acid (90 mg, 0.18 mmol), N-ethylmethylamine (68 mg, 1.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (170 mg, 0.89 mmol) and HOAT (48 mg, 0. The product was dissolved in dichloromethane (5 mL) and cooled to 0°C. DIPEA (114 mg, 0.88 mmol) was added and reacted at room temperature for 5.5 h. Water (20 mL) was added and the product was extracted with dichloromethane (5 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain 71 mg of a white viscous product with a yield of 73% and a purity of 98.69%.

[0537] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.13 (d, J = 8.0 Hz, 1H), 7.07 (br.s, 1H), 6.81 (s, 2H), 6.62 (t, J F-H =75.6Hz,1H),4.25–4.32(m,1H),4.05–4.12(m,2H),3.88–3.94(m,1H),3.89(d,J=6.9Hz, 2H),3.67–3.75(m,1H),3.36–3.45(m,3H),3.14–3.28(m,2H),3.04(s,1.5H),2.92(s,1.5H ),2.77–2.87(m,2H),2.57–2.69(m,2H),2.14(s,3H),1.68–1.82(m,5H),1.26–1.34(m,1H ),1.22(t,J=6.6Hz,1.5H),1.10(t,J=6.6Hz,1.5H),0.63–0.70(m,2H),0.34–0.41(m,2H).

[0538] MS-ESI: m / z 551.10[M+H] + .

[0539] Example 27: 1-(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl)urea

[0540]

[0541] The compound 2-hydroxymethyl-5-aminophenylboronic acid half ester (47 mg, 0.32 mmol) was dissolved in dry tetrahydrofuran (5 mL), and DIPEA (44 mg, 0.34 mmol) and 4-nitrophenyl chloroformate (62 mg, 0.31 mmol) were added. The reaction was carried out at room temperature for 3.5 h. 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (100 mg, 0.28 mmol) was added. The reaction was carried out at room temperature for 5.5 h. Water (10 mL) was added and the mixture was extracted with EtOAc (5 mL×3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to give 43 mg of a white solid with a yield of 28%.

[0542] 1 H NMR (400MHz, CD3OD) δ (ppm): 7.58–7.69 (m, 2H), 7.05–7.14 (m, 3H), 6.93 (d, J = 6.4Hz, 1H), 6.74 (t, J F-H =75.6Hz,1H),5.06(s,2H),4.25–4.33(m,1H),4.04–4.08(m,1H),3.89(d,J=6.7Hz,2H),3.65–3.70(m,1H),3.43–3.56(m,2H), 3.29–3.40(m,1H),2.51–2.59(m,1H),2.14(s,3H),2.00–2.10(m,1H),1.23–1.34(m,1H),0.57–0.62(m,2H),0.30–0.34(m,2H).

[0543] MS(ESI,pos.ion)m / z:530.30[M+H] + .

[0544] Example 28: 1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-5-yl(((2R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamate

[0545]

[0546] The compound 2-hydroxymethyl-5-hydroxyphenylboronic acid half ester (47 mg, 0.31 mmol) was dissolved in dry tetrahydrofuran (5 mL), and DIPEA (44 mg, 0.34 mmol) and 4-nitrophenyl chloroformate (62 mg, 0.31 mmol) were added. The reaction was carried out at room temperature for 3 h. 1-((2R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (100 mg, 0.28 mmol) was added. The reaction was carried out at room temperature for 5 h. Water (10 mL) was added and the mixture was extracted with EtOAc (5 mL×3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 40 / 1) to obtain 28 mg of a white solid with a yield of 18% and a purity of 99.05%.

[0547] 1 H NMR (400MHz, CD3OD) δ (ppm): 7.57–7.73 (m, 2H), 7.05–7.14 (m, 3H), 6.93 (d, J = 6.4Hz, 1H), 6.74 (t, J F-H =75.6Hz,1H),5.06(s,2H),4.25–4.33(m,1H),4.03–4.08(m,1H),3.89(d,J=6.7Hz,2H),3.66–3.71(m,1H),3.44–3.56(m,2H),3.3 3–3.40(m,1H),2.53–2.58(m,1H),2.14–2.23(m,3H),1.99–2.11(m,1H),1.22–1.31(m,1H),0.57–0.62(m,2H),0.30–0.34(m,2H).

[0548] MS(ESI,pos.ion)m / z:531.30[M+H] + .

[0549] Example 37: N-(((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-2-ethoxybenzamide

[0550]

[0551] Step 1: Synthesis of compound (S)-1-tert-butyl 2-methyl 4-((trifluoromethyl)sulfonyl)oxy-1H-pyrrole-1,2(2H,5H)-dicarboxylate

[0552] Compound (2S)-1-tert-butyloxycarbonyl-4-oxoproline methyl ester (7.75 g, 31.9 mmol) and N,N-diisopropylethylamine (15.0 mL, 88.9 mmol) were dissolved in dichloromethane (50 mL). A solution of trifluoromethanesulfonic anhydride (10.5 mL, 59.3 mmol) in dichloromethane (20 mL) was added dropwise at -15°C and stirred at room temperature for 2 h. Dichloromethane (100 mL) was added to dilute the mixture. The organic phase was washed with saturated brine (100 mL x 3), adjusted to pH 1 with hydrochloric acid (2 mol / L), then washed with saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: 60-90 petroleum ether / ethyl acetate (v / v) = 10 / 1) to yield a yellow liquid (11.1 g, 93% yield).

[0553] 1 H NMR(400MHz, CDCl3)δ(ppm):5.79–5.66(m,1H),5.09–4.97(m,1H),4.44–4.33(m,1H),4.33–4.22(m,1H),3.76(s,3H),1.47(s,4H),1.42(s,5H).

[0554] MS-ESI: m / z 320.40[M-55] + .

[0555] Step 2: Synthesis of compound (S)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate

[0556] Compound (S)-1-tert-butyl 2-methyl 4-((trifluoromethyl)sulfonyl)oxy-1H-pyrrole-1,2(2H,5H)-dicarboxylate (11.0 g, 29.3 mmol), bipyraclostrobin (8.92 g, 35.1 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium dichloromethane complex (1.23 g, 1.47 mmol) and potassium acetate (3.47 g, 35.4 mmol) were dissolved in anhydrous 1,4-dioxane (95 mL) and stirred at 100 °C for 3 h under nitrogen protection. The mixture was concentrated under reduced pressure, ethyl acetate (200 mL) was added, and the mixture was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: 60-90 petroleum ether / ethyl acetate (v / v) = 4 / 1) to give a yellow transparent liquid (10.0 g, yield 97%).

[0557] 1H NMR (400MHz, CDCl3) δ (ppm): 6.37–6.24 (m, 1H), 5.14–4.94 (m, 1H), 4.36–4.22 (m, 2H), 3.70 (d, J = 4.7Hz, 3H), 1.44 (s, 5H), 1.39 (s, 4H), 1.24 (s, 12H).

[0558] MS-ESI: m / z 216.10[M-137] + .

[0559] Step 3: Synthesis of compound (S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate

[0560] Compound (S)-1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (8.51 g, 21.7 mmol), 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-iodobenzene (8.40 g, 24.7 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium dichloromethane complex (850 mg, 1.02 mmol) and potassium phosphate (13.0 g, 61.2 mmol) were dissolved in anhydrous 1,4-dioxane (80 mL) and stirred at 100°C for 3 h under nitrogen protection. The mixture was concentrated under reduced pressure, ethyl acetate (200 mL) was added, and the mixture was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (eluent: 60-90 petroleum ether / ethyl acetate (v / v) = 8 / 1) to give a yellow liquid (8.23 g, yield 86%).

[0561] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.13 (d, J = 8.2Hz, 1H), 6.99–6.86 (m, 2H), 6.62 (t, J = 75.4Hz, 1H), 6.04–5.97 (m, 1H), 5.19–5.08 (m, 1H), 4 .66–4.43(m,2H),3.89–3.84(m,2H),3.75(s,3H),1.51(s,3H),1.44(s,6H),1.28–1.24(m,1H),0.70–0.60(m,2H),0.39–0.31(m,2H).

[0562] MS-ESI: m / z 384.10 [Mt-Bu+2H] + .

[0563] Step 4: Synthesis of compound (2S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrole-1,2-dicarboxylate

[0564] Compound (S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (3.72 g, 8.47 mmol) and 10% palladium on carbon (405 mg) were added to methanol (250 mL) and stirred under a hydrogen atmosphere for 12 hours. The solid was filtered through celite, and the mixture was concentrated under reduced pressure to give a yellow liquid (3.49 g, 93% yield).

[0565] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.09 (d, J = 8.0 Hz, 1H), 6.83–6.75 (m, 2H), 6.59 (t, J = 7 5.6Hz,1H),4.42–4.26(m,1H),4.07–3.89(m,1H),3.88–3.81(m,2H),3.79–3.67(m ,3H),3.46–3.37(m,1H),3.37–3.24(m,1H),2.71–2.57(m,1H),2.09–1.92(m,1H), 1.46(s,3H),1.42(s,6H),1.31–1.21(m,1H),0.68–0.59(m,2H),0.39–0.29(m,2H).

[0566] MS-ESI: m / z 386.50 [Mt-Bu+2H] + .

[0567] Step 5: Synthesis of compound (2S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxymethylpyrrolidine-1-carboxylate

[0568] Compound (2S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-1,2-dicarboxylate (1.70 g, 3.85 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). A solution of lithium borohydride (140 mg, 5.78 mmol) was added portionwise and stirred at room temperature for 12 h. The solvent was removed under reduced pressure, and saturated brine (20 mL) was added to the residue. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: 60-90 petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain a colorless, transparent liquid (1.10 g, 69% yield).

[0569] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.09 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 2H), 6.58 (t, J=76.5Hz,1H),5.16(s,1H),4.15–3.99(m,1H),3.94(s,1H),3.85(d,J=6.9Hz,2H), 3.80–3.72(m,1H),3.73–3.60(m,1H),3.29–3.10(m,2H),2.47–2.29(m,1H),1.72– 1.55(m,1H),1.47(s,9H),1.27–1.20(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).

[0570] MS-ESI: m / z 358.10[M- t Bu+2H] + .

[0571] Step 6: Synthesis of compound (2S)-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate

[0572] Compound (2S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxymethylpyrrolidine-1-carboxylate (1.11 g, 2.68 mmol) and triethylamine (750 μL, 5.35 mmol) were dissolved in ethyl acetate (20 mL). A solution of methanesulfonyl chloride in ethyl acetate (7.3 mL, 3.48 mmol, 0.48 mol / L) was slowly added dropwise at 0°C. The mixture was stirred at room temperature for 3 h. The solid was filtered and washed with ethyl acetate (10 mL). The solvent was removed under reduced pressure to obtain (2S)-2-methanesulfonyloxymethyl-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine (1.31 g, 99% yield) as a yellow liquid.

[0573] Compound (2S)-2-methanesulfonyloxymethyl-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine (1.19 g, 2.42 mmol) and sodium azide (490 mg, 7.31 mmol) were dissolved in anhydrous N,N-dimethylformamide (12 mL) and stirred at 80°C for 3 h. The N,N-dimethylformamide was removed under reduced pressure, and the mixture was diluted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (20 mL × 3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: 60-90 petroleum ether / ethyl acetate (v / v) = 8 / 1) to obtain a yellow liquid (1.05 g, 99% yield).

[0574] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.11 (d, J = 7.9Hz, 1H), 6.86–6.80 (m, 2H), 6.60 (t, J = 75.7Hz, 1H), 4.17–3.93 (m, 3H), 3.87 (d, J = 6.4Hz, 2H), 3.50 –3.30(m,1H),3.29–3.12(m,2H),2.52–2.31(m,1H),2.10–1.95(m,1H) ,1.48(s,9H),1.35–1.23(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).

[0575] MS-ESI: m / z 383.20 [Mt-Bu+2H] + .

[0576] Step 7: Synthesis of compound (2S)-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (11162-4)

[0577] Compound (2S)-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-1-carboxylate (1.03 g, 2.35 mmol) was dissolved in DCM (7 mL). A solution of hydrogen chloride in dioxane (10.0 mL, 40.0 mmol, 4 mol / L) was added and stirred at room temperature for 3 h. The solvent was removed under reduced pressure to obtain a brown viscous liquid (889 mg, 99% yield).

[0578] MS-ESI: m / z 339.20 [M-HCl+H] + .

[0579] Step 8: Synthesis of compound 1-((2S)-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethyl ketone

[0580] Compound (2S)-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (880 mg, 2.35 mmol) and triethylamine (992 uL, 7.05 mmol) were dissolved in dichloromethane (23 mL). Acetyl chloride (251 uL, 3.52 mmol) was slowly added dropwise at 0°C and stirred at room temperature for 3 h. Saturated brine (20 mL) was added, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 70 / 1) to obtain a yellow viscous liquid (702 mg, 79% yield).

[0581] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.12 (d, J = 7.9 Hz, 1H), 6.88–6.79 (m, 2H), 6.60 (t, J =75.6Hz,1H),4.32–4.23(m,1H),4.16–4.08(m,1H),3.92–3.84(m,1H),3.88(d, J=6.9Hz,2H),3.46–3.34(m,2H),3.31–3.20(m,1H),2.48–2.37(m,1H),2.16–2. 06(m,1H),2.09(s,3H),1.30–1.24(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).

[0582] MS-ESI: m / z 381.20[M+H] + .

[0583] Step 9: Synthesis of compound 1-((2S)-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethyl ketone hydrochloride

[0584] The compound 1-((2S)-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethyl ketone (399 mg, 1.05 mmol) and triphenylphosphine (3413 mg, 1.58 mmol) were dissolved in tetrahydrofuran / water (8 mL, (v / v) = 3 / 1) and stirred at 50°C for 3 h. The tetrahydrofuran was removed under reduced pressure, and saturated brine (10 mL) was added. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 8 / 1) to obtain a yellow viscous liquid. A solution of hydrogen chloride in dioxane (1 mL, 4 mol / L) was added, stirred, and the solvent was removed under reduced pressure to obtain a yellow viscous liquid (119 mg, 29% yield).

[0585] MS-ESI: m / z 355.15 [M-HCl+H] + .

[0586] Step 10: Synthesis of compound N-(((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidin-2-yl)methyl)-2-ethoxybenzamide

[0587] The compound 1-((2S)-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethyl ketone hydrochloride (40 mg, 0.10 mmol), o-ethoxybenzoic acid (18 uL, 0.12 mmol) and N-hydroxy-7-azabenzotriazole (29 mg, 0.21 mmol) were dissolved in dichloromethane (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (59 mg, 0.31 mmol) and N,N-diisopropylethylamine (67 uL, 0.41 mmol) were added in an ice bath and stirred at room temperature for 5 h. Saturated brine (20 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 50 / 1) to give a yellow liquid (19 mg, yield 37%).

[0588] 1H NMR (600MHz, CDCl3) δ (ppm): 8.45 (t, J=5.6Hz, 1H), 8.15 (dd, J=7.8, 1.7Hz, 1H), 7.46–7.37 (m, 1H), 7.09–7.01 (m, 2H), 6.9 5(d,J=8.3Hz,1H),6.77(d,J=1.6Hz,1H),6.76–6.72(m,1H),6.56(t,J=75.7Hz,1H),4.32–4.15(m,3H),4.03–3.91(m,1H), 3.91–3.81(m,2H),3.77(q,J=6.1Hz,2H),3.36(t,J=10.8Hz,1H),3.26–3.15(m,1H),2.55–2.48(m,1H),2.22(s,0.7H),2. 10(s,2.3H),2.06(td,J=12.6,9.6Hz,1H),1.48(t,J=7.0Hz,3H),1.26–1.22(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).

[0589] MS-ESI: m / z 503.20[M+H] + .

[0590] Example 38: Synthesis of N 2 -(((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Methylpyridine-2,5-dicarboxamide

[0591]

[0592] Step 1: Synthesis of methyl 6-((((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate

[0593] Compound 1-((2S)-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethyl ketone hydrochloride (105 mg, 0.27 mmol, see Example 37 Step 9), 2,5-pyridinedicarboxylic acid-5-methyl ester (56 mg, 0.30 mmol) and N-hydroxy-7-azabenzotriazole (70 mg, 0.51 mmol) were dissolved in dichloromethane (10 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 mg, 0.77 mmol) and N,N-diisopropylethylamine (169 uL, 1.02 mmol) were added in an ice bath and stirred at room temperature for 5 h. Saturated brine (20 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 70 / 1) to give a red liquid (75 mg, yield 54%).

[0594] 1 H NMR(400MHz, CDCl3)δ(ppm):9.19–9.08(m,1H),8.43(dd,J=8.1,2.0Hz,1H),8.25(d,J=8.1Hz,1H),7.58–7.42( m,1H),7.09(d,J=8.2Hz,1H),6.82–6.74(m,2H),6.58(t,J=75.6Hz,1H),4.35–4.25(m,1H),4.08–4.00(m,1H),3 .97(s,3H),3.95–3.88(m,1H),3.82(d,J=6.9Hz,2H),3.68–3.57(m,1H),3.42(t,J=10.8Hz,1H),3.31–3.19(m,1 H),2.78–2.52(m,1H),2.16(s,3H),2.04–1.89(m,1H),1.31–1.21(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).

[0595] MS-ESI: m / z 518.35[M+H] + .

[0596] Step 2: Synthesis of 6-((((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinic acid

[0597] Methyl 6-((((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate (70 mg, 0.14 mmol) and lithium hydroxide monohydrate (11 mg, 0.26 mmol) were dissolved in tetrahydrofuran / water (6 mL, (v / v) = 5 / 1) and stirred at room temperature for 3 h. The tetrahydrofuran was removed under reduced pressure, and the residue was diluted with ethyl acetate (50 mL). The pH was adjusted to 1 with hydrochloric acid (2 mol / L), washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a white solid (68 mg, 99% yield).

[0598] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.77 (s, 1H), 9.50 (s, 1H), 8.48 (d, J = 7.5Hz, 1H), 8.24 (d, J = 8.0Hz, 1 H),7.57–7.42(m,1H),7.14(d,J=8.4Hz,1H),6.84–6.77(m,2H),6.61(t,J=75.5Hz,1H),4.56–4. 46(m,1H),4.05–3.95(m,2H),3.88(d,J=6.8Hz,2H),3.55–3.41(m,2H),3.31(s,1H),2.76–2.61( m,1H),2.37(s,3H),1.95–1.81(m,1H),1.34–1.22(m,1H),0.67–0.55(m,2H),0.35–0.26(m,2H).

[0599] MS-ESI: m / z 504.20[M+H] + .

[0600] Step 3: Compound N 2 -(((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Synthesis of methylpyridine-2,5-dicarboxamide

[0601] Compound 6-((((2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinic acid (60 mg, 0.12 mmol), N-methylethylamine (20 uL, 0.23 mmol) and N-hydroxy-7-azabenzotriazole (32 mg, 0.24 mmol) were dissolved in dichloromethane (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36 mmol) and N,N-diisopropylethylamine (78 uL, 0.42 mmol) were added in an ice bath and stirred at room temperature for 5 h. Saturated brine (20 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1) to give a yellow liquid (20 mg, yield 31%).

[0602] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.08 (s, 1H), 8.64 (s, 1H), 8.21 (d, J = 8.0Hz, 1H), 7.86 (t, J = 7.0Hz, 1H), 7.08 (d, J = 8.0Hz, 1H), 6.8 1–6.75(m,2H),6.58(t,J=75.5Hz,1H),4.33–4.23(m,1H),4.06–3.97(m,1H),3.91(t,J=10.3,7.0Hz,1H),3.83(d,J=6.9Hz,2H ),3.65–3.55(m,2H),3.41(t,J=10.8Hz,1H),3.31–3.19(m,2H),3.09(s,1.6H),2.94(s,1.4H),2.62–2.52(m,1H),2.15(s,3H) ,2.01–1.90(m,1H),1.25(t,J=6.2Hz,1.5H),1.27–1.21(m,1H),1.15(t,J=6.2Hz,1.5H),0.67–0.55(m,2H),0.35–0.26(m,2H).

[0603] MS-ESI: m / z 545.20[M+H] + .

[0604] Example 39: N 2 -(((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5-Methylpyridine-2,5-dicarboxamide

[0605]

[0606] Step 1: Synthesis of compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0607] Compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (11.0 g, 29.43 mmol), pinacol diboron (8.96 g, 35.3 mmol), potassium acetate (8.6 g, 87.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (Pd(dppf)Cl2.CH2Cl2) (2.40 g, 2.94 mmol) were dissolved in dry The reaction mixture was added to a solution of N,N-dimethylformamide (80 mL) and reacted at 100°C under nitrogen for 2 h. The reaction solution was filtered through diatomaceous earth, diluted with 50 mL of ethyl acetate, and washed with saturated brine (50 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EtOAc (v / v) = 10 / 1) to give a green liquid product (10.01 g, yield 99.97%).

[0608] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.39 (d, J = 7.9Hz, 1H), 7.35 (s, 1H), 7.14 (d, J = 7.8Hz, 1H), 6.67 (t, J = 75.6 Hz,1H),3.91(d,J=7.0Hz,2H),1.34(s,12H),1.26–1.32(m,1H),0.69–0.61(m,2H),0.40–0.32(m,2H).

[0609] MS-ESI: m / z 341.15[M+H] + .

[0610] Step 2: Synthesis of (R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate

[0611] The compound 2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 14.7 mmol), (R)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2-(2H,5H)-dicarboxylate (5.00 g, 13.3 mmol, intermediate M), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (Pd(dppf)Cl2.CH2Cl2) (550 mg, 0.67 mmol), and potassium phosphate (K3PO4) (7.60 g, 35.8 mmol) were dissolved in toluene (50 mL) and stirred in an oil bath at 50°C under nitrogen protection for 8 h. The reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate solution (50 ml), and the organic phase was washed with saturated brine (50 ml × 2). The organic phases were combined and dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EtOAc (v / v) = 5 / 1) to give a light yellow viscous liquid (4.60 g, yield 78.60%).

[0612] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.14 (d, J = 8.2Hz, 1H), 6.97–6.90 (m, 2H), 6.63 (t, J = 75.4Hz, 1H), 6.05–5.98 (m, 1H), 5.21–5.09 (m, 1H), 4.67–4.45 (m,2H),3.88(dd,J=11.6,6.9Hz,2H),3.76(d,J=4.3Hz,3H),1.52(s,3H ),1.46(s,6H),1.33–1.25(m,1H),0.69–0.63(m,2H),0.34–0.39(m,2H).

[0613] MS-ESI: m / z 384.10[M-55] + .

[0614] Step 3: Synthesis of (2R,4S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

[0615] (R)-1-tert-Butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2-(2H,5H)-dicarboxylate (4.60 g, 10.5 mmol) was dissolved in methanol (70 mL) and a 10% Pd / C reducing agent (140 mg) was added. The mixture was replaced with hydrogen three times and stirred at room temperature under hydrogen protection for 3 h. The reaction solution was filtered through celite, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EtOAc (v / v) = 6 / 1) to obtain the product as a light yellow viscous liquid (4.60 g, 99.50% yield). Synthesis reference: Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2. J. Med. Chem. 2014, 57, 9042-9064.

[0616] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.10 (d, J=8.0Hz, 1H), 6.81–6.78 (m, 2H), 6.60 (t, J=7 6.4Hz,1H),4.44–4.26(m,1H),4.07–3.90(m,1H),3.90–3.82(m,2H),3.76(d,J=6.5 Hz,3H),3.47–3.37(m,1H),3.38–3.25(m,1H),2.68–2.58(m,1H),2.10–1.95(m,1H ),1.45(d,J=14.1Hz,9H),1.24–1.31(m,1H),0.71–0.59(m,2H),0.41–0.29(m,2H).

[0617] MS-ESI: m / z 386.10[M-55] + :

[0618] Step 4: Synthesis of tert-butyl (2R,4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0619] Dissolve (2R,4S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (1.90 g, 4.301 mmol) in dry tetrahydrofuran (15 mL). Add lithium borohydride (332 mg, 15.6 mmol) under ice-cooling. After addition, move the mixture to room temperature and react for 1 h. Add saturated aqueous sodium chloride (30 mL) and extract with ethyl acetate (30 ml x 2). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a colorless liquid (1.80 g, 100%).

[0620] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.10 (d, J = 8.7Hz, 1H), 6.84–6.78 (m, 2H), 6.59 (t, J F-H =75.6Hz,1H),5.19(d,J=8.7Hz,1H),4.10–4.02(m,1H),4.00–3.91(m,1H),3.86(d,J=6.9Hz,2H),3.82–3.71(m,1H),3.70–3.65(m, 1H),3.27–3.17(m,2H),2.44–2.33(m,1H),1.68–1.58(m,1H),1.48(s,9H),1.34–1.24(m,1H),0.67–0.62(m,2H),0.37–0.33(m,2H).

[0621] MS-ESI: m / z 358.55[M-55] + .

[0622] Step 5: Synthesis of tert-butyl (2R,4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

[0623] The compound (2R,4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.8 g, 4.40 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (880 mg, 8.70 mmol) was added. Methanesulfonyl chloride (702 mg, 6.13 mmol) was added in an ice bath, and the reaction was carried out at room temperature for 3.5 h. Water (30 mL) was added to stop the reaction. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow liquid (2.1 g, yield 98%).

[0624] 1H NMR (400MHz, CDCl3) δ (ppm): 7.12 (d, J = 8.7 Hz, 1H), 6.85–6.81 (m, 2H), 6.62 (t, J F-H =75.7Hz,1H),4.72–4.64(m,0.5H),4.50–4.32(m,1.5H),4.25–3.13(m, 1H),4.00–3.93(m,0.5H),3.89(d,J=6.9Hz,2H),3.82–3.75(m,0.5H),3. 34–3.15(m,2H),3.05–3.03(m,3H),2.60–2.30(m,1H),2.21–2.04(m,1H ),1.50(s,9H),1.35–1.24(m,1H),0.68–0.64(m,2H),0.40–0.35(m,2H).

[0625] MS-ESI: m / z 436.10 [Mt-Bu+2H] + .°

[0626] Step 6: Synthesis of tert-butyl (2R,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate

[0627] The compound (2R,4S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (2.1 g, 4.30 mmol) was dissolved in DMF (11 mL), sodium azide (1.1 g, 17.0 mmol) was added, and the reaction was heated at 80°C for 3.5 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 dried over anhydrous Na2SO4, concentrated, and separated on a silica gel column (eluent: PE / EtOAc (v / v) = 8 / 1) to give a colorless liquid (1.6 g, yield 88%).

[0628] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.11 (d, J = 7.9 Hz, 1H), 6.88–6.79 (m, 2H), 6.60 (t, J F-H=75.7Hz,1H),4.14–3.97(m,3H),3.87(d,J=6.4Hz,2H),3.44–3.33(m,1H),3.26–3.16(m,2H),2.50–2 .32(m,1H),2.06–1.98(m,1H),1.48(s,9H),1.33–1.22(m,1H),0.67–0.62(m,2H),0.38–0.34(m,2H).

[0629] MS-ESI: m / z 383.60[M-55] + .

[0630] Step 7: Synthesis of compound (2R,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride

[0631] Compound (2R,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.66 g, 3.79 mmol) was dissolved in dichloromethane (20 mL), and a 3 mol / L HCl solution in 1,4-dioxane (6 mL) was added. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give a colorless liquid (1.40 g, yield 99%).

[0632] 1 H NMR (400MHz, CD3OD) δ (ppm): 7.15 (d, J = 8.2Hz, 1H), 7.09 (d, J = 1.9Hz, 1H), 6.94 (dd, J = 8.2, 1.9Hz,1H),6.76(t,J=75.5Hz,1H),4.01–3.98(m,1H),3.96(d,J=6.9Hz,2H),3.94–3.91(m ,1H),3.81–3.78(m,1H),3.76–3.73(m,1H),3.65–3.59(m,1H),3.28(t,J=11.2Hz,1H),2.5 7–2.53(m,1H),1.99–1.94(m,1H),1.34–1.29(m,1H),0.67–0.64(m,2H),0.41–0.38(m,2H).

[0633] MS-ESI: m / z 339.15 [M-HCl+H] + .

[0634] Step 8: Synthesis of compound 1-((2R,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0635] The compound (2R,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (1.42 g, 3.79 mmol) was dissolved in dichloromethane (20 mL) and cooled in an ice bath. N,N-diisopropylethylamine (1.9 g, 15.0 mmol) and acetyl chloride (653 mg, 8.32 mmol) were added. The reaction was stopped after stirring at room temperature for 1.5 h. Water (20 mL) was added and stirred for 2 min. The organic phase was separated and dried over anhydrous Na2SO4. The concentrate was separated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 / 1) to give a light brown liquid (1.29 g, yield 90%).

[0636] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.13 (d, J = 8.1Hz, 1H), 6.85 (s, 1H), 6.84 (d, J = 7.4Hz, 1H), 6.61(t,J=75.6Hz,1H),4.31–4.25(m,1H),4.13(dd,J=12.4,4.7Hz,1H),3.93–3.85(m, 1H),3.89(d,J=6.9Hz,2H),3.45–3.36(m,2H),3.30–3.21(m,1H),2.46–2.39(m,1H),2. 15–2.06(m,1H),2.10(s,3H),1.34–1.24(m,1H),0.68–0.64(m,2H),0.38–0.35(m,2H).

[0637] MS-ESI: m / z 381.20[M+H] + .

[0638] Step 9: Synthesis of compound 1-((2R,4S)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride

[0639] The compound 1-((2R,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (1.2 g, 3.20 mmol) and triphenylphosphine (1.1 g, 4.2 mmol) were dissolved in a mixed solvent of tetrahydrofuran / water (v / v=3 / 1, 40 mL), reacted at 50°C for 1 h, concentrated under reduced pressure, extracted with ethyl acetate (15 mL×3), and the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (eluent: DCM / MeOH (v / v)=10 / 1) to give a light brown liquid. A 1,4-dioxane solution of HCl (2 mL, 4 mol / L) was added, the pH was adjusted to 1, and the mixture was concentrated under reduced pressure to give a light yellow solid (1.14 g, yield 92%).

[0640] 1 H NMR (400MHz, CD3OD) δ (ppm): 7.12 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.75 (t, J F-H =75.7Hz,1H),4.31–4.24(m,1H),4.10–4.06(m,1H),3.95(d,J=6.9Hz,2H),3.56(d,J=10.8Hz,1H),3.46–3.37(m,1H),3.29 –3.19(m,2H),2.64–2.57(m,1H),2.18(s,3H),1.98–1.90(m,1H),1.35–1.27(m,1H),0.67–0.63(m,2H),0.41–0.37(m,2H).

[0641] MS-ESI: m / z 355.10 [M-HCl+H] + .

[0642] Step 10: N 2 -(((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Synthesis of methylpyridine-2,5-dicarboxamide

[0643] The compound 1-((2R,4S)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride (660 mg, 1.69 mmol), 5-(ethyl(methyl)carbamoyl)picolinic acid (452 ​​mg, 2.17 mmol) and 1-hydroxybenzotriazole (342 mg, 2.53 mmol) were dissolved in dry N,N-dimethylformamide (15 ml) solution, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (649 mg, 3.39 mmol) was added. After cooling at 0°C, N-methylmorpholine (553 mg, 5.47 mmol) was added and the reaction was stirred at room temperature for 4 hours. Water (150 mL) was added to stop the reaction. The organic phase was extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH (v / v) = 23 / 1) to give a white solid (632 mg, yield 69%).

[0644] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.11 (s, 1H), 6.87 (s, 1H), 8.23 ​​(d, J = 7.9Hz, 1H), 7.89 (br.s, 1H), 7.11 (d, J = 7.9Hz, 1H), 6.81 (s, 2H), 6.60 (t, J F-H =75.6Hz,1H),4.26–4.36(m,1H),4.00–4.08(m,1H),3.92–3.96(m,1H),3. 86(d,J=6.8Hz,2H),3.59–3.67(m,2H),3.44(t,J=10.7Hz,1H),3.23–3.33 (m,2H),3.12(s,1.7H),2.97(s,1.3H),2.57–2.63(m,1H),2.18(s,3H),1. 92–2.01(m,1H),1.13–1.36(m,4H),0.63–0.69(m,2H),0.35–0.38(m,2H).

[0645] MS-ESI: m / z 545.20[M+H] + .

[0646] Example 40: N 2 -(((2R,4R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Methylpyridine-2,5-dicarboxamide

[0647]

[0648] Step 1: Synthesis of compound (R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester

[0649] Compound (R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (4.6 g, 10.0 mmol, Example 39, Step 2) was dissolved in 50 mL of anhydrous tetrahydrofuran. Lithium borohydride (507 mg, 13.4 mmol) was added in an ice bath and allowed to react at room temperature for 3 h. The reaction was stopped after the reaction was complete. The reaction was quenched by adding an ice-water mixture and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The concentrate was then separated on a silica gel column (eluent: PE / EtOAc (v / v) = 5 / 1) to afford a white foamy solid (3.78 g, 88% yield).

[0650] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.13 (d, J = 8.2Hz, 1H), 6.93–7.00 (m, 1.25H), 6.87–6.89 (m, 0.75 H),6.63(t,J=75.4Hz,1H),6.03(s,0.3H),5.93(s,0.7H),4.89(s,0.8H),4.74(s,0.2H),4.59 –4.66(m,1H),4.40–4.52(m,2H),3.89(d,J=6.9Hz,2H),3.81–3.86(m,1H),3.73–3.79(m,0.3H ),3.64–3.68(m,0.7H),1.53(s,9H),1.29–1.32(m,1H),0.63–0.68(m,2H),0.35–0.38(m,2H).

[0651] MS-ESI: m / z 356.20[M-55] + .

[0652] Step 2: Synthesis of tert-butyl (2R,4R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0653] The compound (R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2.2 g, 5.3 mmol) and (tricyclohexylphosphine)(1,5-cyclooctadiene)(pyridine)iridium hexafluorophosphate (Crabtrees catalyst) (0.66 g, 0.80 mmol) were dissolved in 90 mL of anhydrous dichloromethane. The mixture was reacted at room temperature under a 0.5 MPa hydrogen atmosphere for 72 hours until the starting materials reacted completely and the reaction was stopped. 300 mL of saturated brine was added, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: PE / EtOAc (v / v) = 10 / 1) to obtain a yellow liquid (1.75 g, 76% yield). Synthesis reference: Azacyclic FTY720Analogues that Limit Nutrient Transporter Expression but Lack S1P ReceptorActivity and Negative Chronotropic Effects Offer a Novel and EffectiveStrategy to Kill Cancer Cells in Vivo.ACS Chem.Biol.2016,11,2,409-414.

[0654] 1 H NMR (400MHz, CDCl3) δ (ppm) 7.09 (d, J = 7.9Hz, 1H), 6.76–6.81 (m, 1.75H), 6. 75(s,0.5H),6.59(t,J=75.7Hz,0.75H),4.15–4.23(m,1H),3.85(d,J=6.9Hz ,2H),3.70–3.75(m,3H),3.30–3.46(m,2H),2.08–2.16(m,1H),1.96–2.03(m ,1H),1.47(s,9H),1.27–1.30(m,1H),0.61–0.66(m,2H),0.32–0.36(m,2H).

[0655] MS-ESI: m / z 358.20[M-55] + .

[0656] Step 3: Synthesis of tert-butyl (2R,4R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

[0657] Tert-butyl (2R,4R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.7 g, 3.9 mmol) was dissolved in 30 mL of anhydrous dichloromethane. Methanesulfonyl chloride (MsCl) (1.8 mL, 13.0 mmol) was added in an ice bath and allowed to react at room temperature for 2 h. The reaction was stopped after the reaction was complete. An ice-water mixture was added to quench the reaction, followed by extraction with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: PE / EtOAc (v / v) = 5 / 1) to afford a pale yellow oil (1.95 g, 98% yield).

[0658] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.10 (d, J = 7.9Hz, 1H), 6.77–6.79 (m, 2H), 6.59 (t, J = 75.7 Hz,1H),4.30–4.37(m,1H),4.17–4.26(m,1H),3.86(d,J=6.6Hz,2H),3.74–3.79(m,1H) ,3.40–3.50(m,1H),3.14–3.08(m,2H),3.03(s,3H),2.29–2.38(m,1H),2.14–2.19(m,1 H),1.49(s,4H),1.46(s,5H),1.27–1.34(m,1H),0.62–0.66(m,2H),0.33–0.37(m,2H).

[0659] MS-ESI: m / z 436.10 [Mt-Bu+2H] + .

[0660] Step 4: Synthesis of tert-butyl (2R,4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate

[0661] Tert-butyl (2R,4R)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (1.8 g, 3.7 mmol) and sodium azide (716 mg, 11.0 mmol) were dissolved in 15 mL of N,N-dimethylformamide and heated at 80°C for 4 h. The reaction was stopped after complete reaction. 100 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: PE / EtOAc (v / v) = 5 / 1) to afford a colorless oil (1.3 g, 81% yield).

[0662] 1 H NMR(400MHz, CDCl3)δ7.10(d,J=7.9Hz,1H),6.77–6.79(m,2H),6.59(t,J=75.7Hz,1H),4.08– 4.16(m,0.6H),3.98–4.05(m,0.4H),3.86(d,J=6.2Hz,2H),3.76–3.81(m,1H),3.64–3.71(m,0 .5H),3.47–3.59(m,1H),3.38–3.46(m,2H),3.27–3.32(m,0.5H),2.17–2.27(m,1H),2.07–2. 15(m,1H),1.50(s,4H),1.47(s,5H),1.26–1.32(m,1H),0.62–0.67(m,2H),0.33–0.37(m,2H).

[0663] MS-ESI: m / z 383.40[M-55] + .

[0664] Step 5: Synthesis of (2R,4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride

[0665] Dissolve tert-butyl (2R,4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate (1.3 g, 2.9 mmol) in 30 mL of dichloromethane. Add 1,4-dioxane hydrochloride (5 mL) and allow to react at room temperature for 1 hour. Once the reaction is complete, the reaction is stopped. Remove the solvent by distillation under reduced pressure, and concentrate to yield a yellow liquid (1.1 g, 100% yield).

[0666] 1H NMR (400MHz, CDCl3) δ (ppm): 7.07 (d, J = 8.0Hz, 1H), 6.84 (s, 1H), 6.80 (d, J = 8.1Hz, 1H), 6.57 (t, J = 75.5Hz, 1H), 4.02–4.11 (m, 1H), 3.94–3.99 (m, 1H), 3.85(d,J=6.9Hz,2H),3.78–3.82(m,1H),3.65(s,3H),3.25–3.36(m,1H),2 .22–2.24(m,2H),1.22–1.29(m,1H),0.58–0.62(m,2H),0.30–0.34(m,2H).

[0667] MS-ESI: m / z 339.10 [M-HCl+H] + .

[0668] Step 6: Synthesis of compound 1-((2R,4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0669] Dissolve (2R,4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (4.6 g, 10.0 mmol) in 20 mL of dichloromethane. Add triethylamine (0.8 mL, 6.0 mmol) and acetyl chloride (0.1 mL, 3 mmol) in an ice bath. Allow to react at room temperature for 1 h until the reaction is complete. Stop the reaction. Quench the reaction by adding saturated brine and extract with dichloromethane (20 mL x 3). Dry the organic phase over anhydrous sodium sulfate, remove the solvent, and separate the concentrate on a silica gel column (eluent: PE / EA (v / v) = 2 / 1) to yield a yellow liquid (1.04 g, 93% yield).

[0670] 1H NMR (400MHz, CDCl3) δ (ppm): 7.12 (d, J = 7.9Hz, 1H), 6.78–6.80 (m, 2H), 6.60 (t, J = 75.6Hz, 1 H),4.38–4.41(m,1H),3.89–3.94(m,1H),3.87(d,J=6.9Hz,2H),3.76(dd,J=12.3,6.0Hz,1H ),3.63–3.72(m,1H),3.47(dd,J=12.2,2.8Hz,1H),3.40(t,J=9.8Hz,1H),2.22–2.27(m,1H ),2.13–2.18(m,1H),2.07(s,3H),1.29–1.35(m,1H),0.63–0.68(m,2H),0.34–0.38(m,2H).

[0671] MS-ESI: m / z 380.90[M+H] + .

[0672] Step 7: Synthesis of compound 1-((2R,4R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0673] The compound 1-((2R,4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (1.0 g, 2.63 mmol) was dissolved in a mixture of 30 mL of tetrahydrofuran and 10 mL of water. Triphenylphosphine (1.04 g, 4.0 mmol) was then added and allowed to react at 50°C for 2 h. Once the starting material had reacted completely, the reaction was stopped. 30 mL of saturated brine was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed, and the concentrate was separated on a silica gel column (eluent: DCM / MeOH (v / v) = 20 / 1) to yield a light brown viscous product (0.89 g, 95% yield).

[0674] MS-ESI: m / z 355.10[M+H] + .

[0675] Step 8: Synthesis of compound 1-((2R,4R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride

[0676] Dissolve 1-((2R,4R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (0.88 g, 2.5 mmol) in 30 mL of dichloromethane. Add 1,4-dioxane hydrochloride (2 mL) and allow to react at room temperature for 1 hour. Once the reaction is complete, the reaction is stopped. Remove the solvent by distillation under reduced pressure, and concentrate to yield a brown solid (0.95 g, 98% yield).

[0677] Step 9: Compound N 2 -((((2R,4R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Synthesis of methylpyridine-2,5-dicarboxamide

[0678] Compound 1-((2R,4R)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride (950 mg, 2.43 mmol), 5-(ethyl(methyl)carbamoyl)picolinic acid (603 mg, 2.89 mmol) and 1-hydroxy-7-azobenzotriazole (1.12 g, 7.82 mmol) were dissolved in dichloromethane (40 mL) and cooled in an ice bath. 1-(3-dimethylamino)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride (950 mg, 2.43 mmol) was added. The product was added with 1,2-diisopropyl)-3-ethylcarbodiimide hydrochloride (1.56 g, 7.72 mmol) and N,N-diisopropylethylamine (1.8 mL, 10.0 mmol) at room temperature for 1 h. After the reaction of the starting materials was complete, the reaction was stopped and saturated brine (100 mL) was added. The product was extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a dark red solid (900 mg, yield 68%).

[0679] 1H NMR (400MHz, CDCl3) δ (ppm): 8.76 (s, 1H), 8.64 (s, 1H), 8.20 (d, J = 8.0Hz, 1H), 7.87 (br.s, 1H), 7.11 (d, J = 8.0Hz, 1H),6.80(s,1H),6.49(d,J=9.5Hz,1H),6.59(t,J=75.6Hz,1H),4.49–4.54(m,1H),3.90–3.95(m,1H),3.86(d,J= 6.8Hz,2H),3.76–3.82(m,1H),3.55–3.72(m,4H),3.42(t,J=9.9Hz,1H),3.10(s,2H),2.95(s,1H),2.20–2.26(m, 1H),2.09–2.17(m,1H),2.09(s,3H),1.30–1.34(m,1H),1.11–1.21(m,3H),0.63–0.66(m,2H),0.33–0.37(m,2H).

[0680] MS-ESI: m / z 545.25[M+H] + .

[0681] Example 41: N 2 -(((2S,4R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Methylpyridine-2,5-dicarboxamide

[0682]

[0683] Step 1: Synthesis of (2S,4R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine-1,2-dicarboxylate

[0684] The compound 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (10.410 g, 26.73 mmol) was dissolved in anhydrous tetrahydrofuran (62 mL), cooled to -20°C, and isopropylmagnesium chloride-lithium chloride (22 mL, 29.00 mmol, 1.3 mol / Lin THF) was added dropwise. The mixture was stirred at room temperature for 2 h, stirred at -78°C for 0.5 h, and (2S)-1-tert-butyloxycarbonyl-4-oxoproline methyl ester (5.00 g, 20.60 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise. The mixture was stirred at -70°C for 2 h. The reaction was quenched by adding saturated ammonium chloride solution (5 mL) and diluted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow liquid. Purification by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 4 / 1) gave a yellow transparent liquid (5.21 g, 55.40% yield). Synthesis reference: Synthesis of 4-cis-Phenyl-L-proline via Hydrogenolysis J. Org. Chem. 2001, 66, 3593-3596.

[0685] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.19 (d, J = 14.9Hz, 1H), 7.13 (d, J = 8.3Hz, 1H), 6.95 (d,J=8.3Hz,1H),6.62(t,J=75.6Hz,1H),4.57–4.42(m,1H),3.95–3.84(m,3H), 3.82(d,J=6.0Hz,3H),3.76–3.62(m,1H),2.68–2.58(m,1H),2.33–2.21(m,1H), 1.45(d,J=8.5Hz,9H),1.28–1.24(m,1H),0.69–0.60(m,2H),0.38–0.29(m,2H).

[0686] MS-ESI:m / z 340.10[M-H2O-Boc+2H] + .

[0687] Step 2: Synthesis of (2S,4R)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine-2-carboxylic acid

[0688] (2S,4R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine-1,2-carboxylate (5.21 g, 11.38 mmol) and lithium hydroxide monohydrate (560 mg, 22.91 mmol) were dissolved in tetrahydrofuran / water (13 mL, (v / v) = 5 / 1) and stirred at room temperature for 4 hours. The mixture was cooled in an ice bath for 10 minutes, and dilute hydrochloric acid (4 mol / L) was added dropwise to adjust the pH to 4. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light brown solid (5.15 g, 100% yield).

[0689] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.14–7.05 (m, 2H), 6.93 (d, J = 8.2Hz, 1H), 6.61 (t, J = 75.6Hz, 1H), 4.58–4.46 (m, 2H), 3.91–3.82 (m, 2H), 3.82–3.7 0(m,1H),3.67–3.50(m,1H),2.64–2.52(m,1H),2.47(d,J=13.6Hz,1H) ,1.41(s,9H),1.27–1.22(m,1H),0.66–0.54(m,2H),0.39–0.25(m,2H).

[0690] MS-ESI:m / z 370.10[M-H2O-tBu+2H] + .

[0691] Step 3: Synthesis of (1R,4S)-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate

[0692] The compound (2S,4R)-1-tert-butoxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.10 g, 11.50 mmol) and N,N-diisopropylethylamine (5.6 mL, 34.00 mmol) were dissolved in dichloromethane (45 mL). Methanesulfonyl chloride (1.3 mL, 17.00 mmol) was slowly added dropwise at 0°C and stirred at room temperature for 2 h. Dichloromethane (100 mL) was added to dilute the mixture. The organic phase was washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow liquid. Purification by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 5 / 1) gave a yellow liquid (3.19 g, 65.20% yield).

[0693] 1 H NMR (400MHz, CDCl3): δ7.19(d,J=8.3Hz,1H),7.07(d,J=1.9Hz,1H),6.93(dd,J=8.3,2.0Hz,1H),6.64(t,J=75.2Hz,1H),4.69(br.s,1H),3.88(d,J= 6.9Hz,2H),3.70–3.58(m,2H),2.42(d,J=11.9Hz,1H),2.27(d,J=10.6Hz, 1H),1.47(s,9H),1.29–1.24(m,1H),0.67–0.61(m,2H),0.38–0.32(m,2H).

[0694] MS-ESI: m / z 370.10 [M-tBu+2H] + .

[0695] Step 4: Synthesis of compound (2S)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid

[0696] Dissolve (1R,4S)-tert-butyl 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate (3.15 g, 7.40 mmol) in dichloromethane (85 mL). Add trifluoroacetic acid (5.6 mL, 34.00 mmol) in dichloromethane (20 mL) dropwise, and stir at room temperature for 2.5 hours. The organic phase is washed with water (80 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow liquid. Purify by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 5 / 1) to obtain a yellow solid (1.53 g, 48.50%).

[0697] MS-ESI: m / z 370.10 [M-tBu+2H] + .

[0698] Step 5: Synthesis of (2S,4R)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid

[0699] Compound (2S)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (640 mg, 1.50 mmol) was dissolved in ethanol (31 mL). Pd / C (520 mg, 10% Pd, 55% H2O) and triethylamine (319 μL, 2.29 mmol) were added. The mixture was stirred at room temperature for 17 hours under a hydrogen atmosphere with the exclusion of air. The reaction mixture was filtered through celite to remove the solids, and the solvent was removed from the filtrate under reduced pressure to yield a colorless, transparent liquid (645 mg, 100% yield). Synthesis reference: Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2. J. Med. Chem. 2014, 57, 9042-9064.

[0700] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.03 (d, J = 8.1Hz, 1H), 6.82 (d, J = 9.1Hz, 1H), 6.77 (d, J=7.4Hz,1H),6.55(t,J=75.8Hz,1H),4.25–4.19(m,1H),4.04–3.85(m,1H),3.88– 3.80(m,2H),3.38(t,J=10.7Hz,1H),3.27–3.15(m,1H),2.72–2.55(m,1H),2.07–1 .92(m,1H),1.41(s,9H),1.28–1.20(m,1H),0.63–0.56(m,2H),0.34–0.28(m,2H).

[0701] MS-ESI:m / z372.05[Mt-Bu+2H] + .

[0702] Step 6: Synthesis of (2S,4R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

[0703] Compound (2S,4R)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid (920 mg, 2.15 mmol), methanol (175 uL, 4.32 mmol) and 1-hydroxybenzotriazole (445 mg, 3.23 mmol) were dissolved in N,N-dimethylformamide (15 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (622 mg, 3.23 mmol) and N-methylmorpholine (480 uL, 4.30 mmol) were added in an ice bath and stirred at room temperature for 12 h. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 5 / 1) to give a colorless transparent liquid (764 mg, yield 80.39%).

[0704] MS-ESI: m / z 386.05 [Mt-Bu+2H] + .

[0705] Step 7: Synthesis of compound (2S,4R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0706] Compound (2S,4R)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (212-1) (760 mg, 1.72 mmol) was dissolved in anhydrous tetrahydrofuran (7 mL). Lithium borohydride (68 mg, 2.81 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 3.5 h. Saturated ammonium chloride (20 mL) was added to quench the lithium borohydride, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 4 / 1) to obtain a colorless, transparent liquid (518 mg, 1.25 mmol, 72.77% yield).

[0707] 1H NMR (400MHz, CDCl3) δ (ppm): 7.08 (d, J = 8.1Hz, 1H), 6.79 (s, 1H), 6.78 (d, J = 6.7Hz, 1H), 6. 58(t,J=75.7Hz,1H),5.18(d,J=8.2Hz,1H),4.07–4.00(m,1H),3.99–3.89(m,1H),3.85(d, J=6.9Hz,2H),3.80–3.70(m,1H),3.70–3.62(m,1H),3.28–3.12(m,2H),2.46–2.30(m,1H) ,1.69–1.57(m,1H),1.47(s,9H),1.28–1.23(m,1H),0.67–0.59(m,2H),0.38–0.30(m,2H).

[0708] MS-ESI: m / z 358.20 [Mt-Bu+2H] + .

[0709] Step 8: Synthesis of (2S,4R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

[0710] Compound (2S,4R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (212-2) (510 mg, 1.23 mmol) and N,N-diisopropylethylamine (612 uL, 3.70 mmol) were dissolved in dichloromethane (5 mL). Methanesulfonyl chloride (114 uL, 1.85 mmol) was slowly added dropwise at 0°C and stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 4 / 1) to obtain a yellow liquid (606 mg, 99.97% yield).

[0711] MS-ESI: m / z 436.10 [Mt-Bu+2H] + .

[0712] Step 9: Synthesis of (2S,4R)-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate

[0713] The compound (2S,4R)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (590 mg, 1.20 mmol) and sodium azide (241 mg, 3.60 mmol) were dissolved in anhydrous N,N-dimethylformamide (6 mL) and stirred at 80°C for 2 h. The N,N-dimethylformamide was removed under reduced pressure, and the residue was diluted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (30 mL × 3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 5 / 1) to give a yellow liquid (308 mg, 58.51%).

[0714] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.10 (d, J = 7.9Hz, 1H), 6.86–6.79 (m, 2H), 6.59 ( t,J=75.7Hz,1H),4.18–3.93(m,2.6H),3.87(d,J=6.4Hz,2H),3.73–3.63(m, 0.4H),3.48–3.31(m,1H),3.29–3.15(m,2H),2.50–2.31(m,1H),2.08–1.95( m,1H),1.47(s,9H),1.31–1.24(m,1H),0.67–0.62(m,2H),0.37–0.33(m,2H).

[0715] MS-ESI: m / z 383.10 [Mt-Bu+2H] + .

[0716] Step 10: Synthesis of compound (2S,4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride

[0717] Dissolve (2S,4R)-tert-butyl 2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate (270 mg, 0.62 mmol) in DCM (6 mL). Add hydrogen chloride in dioxane (1.5 mL, 6.00 mmol, 4 mol / L) and stir at room temperature for 2 h. Remove the solvent under reduced pressure to obtain a yellow viscous solid (230 mg, 99.66% yield).

[0718] 1H NMR (400MHz, CDCl3) δ (ppm): 7.11 (d, J = 8.1Hz, 1H), 6.90 (s, 1H), 6.83 (d, J = 8 .2Hz,1H),6.59(t,J=75.5Hz,1H),4.05–3.93(m,2H),3.87(d,J=6.9Hz,2H), 3.82–3.72(m,2H),3.59–3.47(m,1H),3.45–3.32(m,1H),2.53–2.43(m,1H), 2.06–1.91(m,1H),1.32–1.22(m,1H),0.69–0.57(m,2H),0.41–0.31(m,2H).

[0719] MS-ESI: m / z 339.15 [M-HCl+H] + .

[0720] Step 11: Synthesis of compound 1-(2S,4R)-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone

[0721] (2S,4R)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (220 mg, 0.59 mmol) was dissolved in dichloromethane (6 mL). Triethylamine (248 μL, 1.76 mmol) and acetyl chloride (62 μL, 0.87 mmol) were slowly added dropwise at 0°C. The mixture was stirred at room temperature for 2 h. Saturated brine (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 1 / 1) to yield a yellow liquid (180 mg, 80.61% yield).

[0722] 1H NMR (400MHz, CDCl3) δ (ppm): 7.11 (d, J=7.9Hz, 1H), 6.84 (s, 1H), 6.83–6.80 (m, 1H), 6.60(t,J=75.6Hz,1H),4.30–4.21(m,1H),4.15–4.08(m,1H),3.92–3.88(m,1H),3. 87(d,J=6.9Hz,2H),3.45–3.34(m,2H),3.30–3.20(m,1H),2.46–2.37(m,1H),2.09( s,3H),2.08–2.02(m,1H),1.31–1.25(m,1H),0.68–0.61(m,2H),0.38–0.32(m,2H).

[0723] MS-ESI: m / z 381.15[M+H] + .

[0724] Step 12: Synthesis of compound 1-(2S,4R)-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride

[0725] Palladium on carbon (18 mg, 10% Pd, 55% H2O) was added to 1-(2S,4S)-2-azidomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (180 mg, 0.47 mmol) in methanol (5 mL). The mixture was stirred at room temperature for 2 hours. A solution of hydrogen chloride in dioxane (0.5 mL, 2.00 mmol, 4 mol / L) was then added. The reaction mixture was filtered through celite to remove the palladium on carbon. The solvent was removed under reduced pressure to yield a yellow viscous liquid (185 mg, 100% yield).

[0726] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.15–7.04 (m, 2H), 6.94–6.90 (m, 1H), 6.73 (t, J = 7 5.7Hz,1H),4.36–4.21(m,1H),4.12–4.00(m,1H),3.93(d,J=6.2Hz,2H),3.77–3 .66(m,1H),3.67–3.52(m,2H),3.46–3.32(m,1H),2.65–2.52(m,1H),2.16(s,3 H),2.00–1.87(m,1H),1.32–1.24(m,1H),0.67–0.58(m,2H),0.42–0.33(m,2H).

[0727] MS-ESI: m / z 355.10 [M-HCl+H] + .

[0728] Step 13: Compound N 2 -(((2S,4R)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -methyl-N 5 Synthesis of 2,5-ethylpyridine dicarboxamide

[0729] The compound 1-(2S,4R)-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride (150 mg, 0.38 mmol), 5-(ethyl(methyl)carbamoyl)picolinic acid (88 mg, 0.42 mmol) and 1-hydroxybenzotriazole (79 mg, 0.57 mmol) were dissolved in N,N-dimethylformamide (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (111 mg, 0.58 mmol) and N-methylmorpholine (86 uL, 0.77 mmol) were added in an ice bath and stirred at room temperature for 15 h. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 3 / 2) to give a white solid (118 mg, yield 56.45%).

[0730] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.08 (s, 1H), 8.64 (s, 1H), 8.20 (d, J = 8.0Hz, 1H), 7.86 (t, J = 7.0Hz, 1H), 7.08 (d, J = 8.0Hz ,1H),6.81–6.76(m,2H),6.58(t,J=75.6Hz,1H),4.34–4.24(m,1H),4.05–3.97(m,1H),3.95–3.87(m,1H),3.83(d,J=6 .9Hz,2H),3.66–3.46(m,2H),3.41(t,J=10.8Hz,1H),3.27–3.20(m,2H),3.09(s,1.7H),2.94(s,1.3H),2.64–2.52(m, 1H),2.15(s,3H),2.00–1.92(m,1H),1.27–1.23(m,2.5H),1.18–1.10(m,1.5H),0.68–0.58(m,2H),0.39–0.30(m,2H).

[0731] MS-ESI: m / z 545.20[M+H] + .

[0732] Example 42: N 2 -(((2S,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Methylpyridine-2,5-dicarboxamide

[0733]

[0734] Step 1: Synthesis of compound (2S)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid

[0735] Compound (2S)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (1.04 g, 2.45 mmol, Step 4 of Example 41), tris(triphenylphosphine)rhodium chloride (295 mg, 0.32 mmol), triethylamine (490 uL, 3.52 mmol), and anhydrous tetrahydrofuran (2 mL) were dissolved in anhydrous ethanol (18 mL), and the mixture was stirred at room temperature for 4 days under a hydrogen atmosphere (0.8 MPa) with the air excluded. The solvent was concentrated, and the residue was diluted with ethyl acetate (50 mL). The pH was adjusted to 1 with dilute hydrochloric acid (1 mol / L). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated to obtain a yellow liquid. This was purified by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 5:1) to obtain a white viscous solid (843 mg, 80.45% yield). Synthesis reference: Carboxylate-Directed Highly Stereoselective Homogeneous Hydrogenation of Cyclic Olefins with Wilkinson's Catalyst. Organic Letters. 2003 Vol. 5, No. 91587-1589.

[0736] 1H NMR(400MHz, CDCl3)δ(ppm):7.15–7.06(m,1H),6.85–6.73(m,2H),6.59(t, J=75.6Hz,1H),4.56–4.30(m,1H),4.09–3.92(m,1H),3.92–3.79(m,2H),3. 56–3.38(m,1H),3.39–3.23(m,1H),2.77–2.54(m,1H),2.50–2.14(m,1H),1 .49–1.44(m,9H),1.33–1.18(m,1H),0.68–0.55(m,2H),0.41–0.27(m,2H).

[0737] MS-ESI: m / z 372.05 [Mt-Bu+2H] + .

[0738] Step 2: Synthesis of compound (2S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate

[0739] Compound (2S)-1-tert-butyloxycarbonyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-pyrrolidine-2-carboxylic acid (810 mg, 1.90 mmol), methanol (154 uL, 3.80 mmol) and 1-hydroxybenzotriazole (392 mg, 2.84 mmol) were dissolved in N,N-dimethylformamide (12 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (548 mg, 2.84 mmol) and N-methylmorpholine (430 uL, 3.80 mmol) were added in an ice bath and stirred at room temperature for 13 h. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 5 / 1) to give a colorless transparent liquid (571 mg, yield 68.24%).

[0740] 1H NMR (400MHz, CDCl3) δ (ppm): 7.08 (d, J = 8.0Hz, 1H), 6.80–6.75 (m, 2H), 6.58 (t, J = 75.6Hz, 1H), 4.5 3–4.43(m,0.3H),4.40–4.35(m,0.7H),4.04–3.91(m,1H),3.87–3.81(m,2H),3.75(s,3H),3.54–3 .44(m,1H),3.43–3.36(m,0.5H),3.35–3.25(m,0.5H),2.70–2.56(m,0.3H),2.35–2.24(m,1.4H), 2.07–1.93(m,0.3H),1.45–1.42(m,9H),1.29–1.22(m,1H),0.67–0.58(m,2H),0.36–0.29(m,2H).

[0741] MS-ESI: m / z 386.10 [Mt-Bu+2H] + .

[0742] Step 3: Synthesis of compound (2S,4S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0743] Compound (2S)-1-tert-butyl 2-methyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1,2-dicarboxylate (540 mg, 1.22 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). Lithium borohydride (48 mg, 1.98 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. Saturated ammonium chloride (20 mL) was added to quench the lithium borohydride, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 4 / 1) to obtain a colorless, transparent liquid (311 mg, 61.49% yield).

[0744] 1H NMR (400MHz, CDCl3) δ (ppm): 7.09 (d, J = 7.9Hz, 1H), 6.78 (s, 2H), 6.58 (t, J = 75.7Hz, 1H), 4.25–4.12 (m, 1H), 3.85 (d, J = 6.9Hz, 2H), 3.79–3. 63(m,3H),3.49–3.30(m,2H),2.20–2.06(m,1H),2.06–1.96(m,1H),1 .47(s,9H),1.33–1.23(m,1H),0.69–0.59(m,2H),0.39–0.31(m,2H).

[0745] MS-ESI: m / z 358.10 [Mt-Bu+2H] + .

[0746] Step 4: Synthesis of (2S,4S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

[0747] Dissolve (2S,4S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (260 mg, 0.63 mmol) and N,N-diisopropylethylamine (324 uL, 1.96 mmol) in dichloromethane (5 mL). Slowly add methanesulfonyl chloride (76 uL, 0.98 mmol) dropwise at 0°C and stir at room temperature for 2 h. The solvent is removed under reduced pressure, and the residue is separated by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 4 / 1) to obtain a yellow liquid (309 mg, 99.99% yield).

[0748] MS-ESI:m / z436.10[Mt-Bu+2H] + .

[0749] Step 5: Synthesis of (2S,4S)-tert-butyl 2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate

[0750] The compound (2S,4S)-tert-butyl 4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (320 mg, 0.65 mmol) and sodium azide (131 mg, 1.95 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) and stirred at 80°C for 2 h. N,N-dimethylformamide was removed by rotary evaporation under reduced pressure, and the residue was diluted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (30 mL × 3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 5 / 1) to obtain a yellow liquid (189 mg, 66.20% yield).

[0751] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.10 (d, J = 7.9Hz, 1H), 6.79 (s, 2H), 6.60 (t, J = 75.5Hz ,1H),4.17–3.97(m,1H),3.86(d,J=6.2Hz,2H),3.79(t,J=9.1Hz,1H),3.71–3.62( m,0.5H),3.57–3.38(m,3H),3.38–3.27(m,0.5H),2.27–2.16(m,1H),2.15–2.06(m ,1H),1.50–1.47(m,9H),1.30–1.24(m,1H),0.69–0.61(m,2H),0.40–0.30(m,2H).

[0752] MS-ESI: m / z 383.15 [Mt-Bu+2H] + .

[0753] Step 6: Synthesis of compound (2S,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (11213-5)

[0754] Dissolve (2S,4S)-tert-butyl 2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine-1-carboxylate (270 mg, 0.62 mmol) in DCM (6 mL). Add hydrogen chloride in dioxane (1.5 mL, 6.00 mmol, 4 mol / L) and stir at room temperature for 2 h. Remove the solvent under reduced pressure to obtain a yellow solid (270 mg, 99.66% yield).

[0755] 1H NMR (400MHz, CDCl3) δ (ppm): 7.12 (d, J = 8.1Hz, 1H), 6.86 (s, 1H), 6.82 (d, J = 8.2Hz, 1H) ,6.60(t,J=75.5Hz,1H),4.13–4.02(m,1H),4.02–3.94(m,1H),3.88(d,J=6.9Hz,2H), 3.86–3.81(m,1H),3.80–3.73(m,1H),3.68–3.60(m,1H),3.39–3.27(m,1H),2.29–2.2 3(m,1H),2.11–2.02(m,1H),1.29–1.23(m,1H),0.70–0.59(m,2H),0.42–0.32(m,2H).

[0756] MS-ESI: m / z 339.20 [M-HCl+H] + .

[0757] Step 7: Synthesis of compound 1-(2S,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (213-6)

[0758] (2S,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidine hydrochloride (220 mg, 0.59 mmol) and triethylamine (248 uL, 1.76 mmol) were dissolved in dichloromethane (6 mL). Acetyl chloride (62 uL, 0.87 mmol) was slowly added dropwise at 0°C and stirred at room temperature for 2 h. Saturated brine (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 1 / 1) to yield a yellow liquid (171 mg, 76.58% yield).

[0759] 1H NMR (400MHz, CDCl3) δ (ppm): 7.13 (d, J = 7.9Hz, 1H), 6.81 (s, 2H), 6.62 (t, J = 75.6Hz, 1H),4.44–4.37(m,1H),3.97–3.90(m,1H),3.88(d,J=6.9Hz,2H),3.79–3.74(m,1H), 3.70–3.62(m,1H),3.52–3.46(m,1H),3.41(t,J=9.7Hz,1H),2.29–2.22(m,1H),2.18 –2.13(m,1H),2.08(s,3H),1.33–1.26(m,1H),0.70–0.63(m,2H),0.40–0.34(m,2H).

[0760] MS-ESI: m / z 381.20[M+H] + .

[0761] Step 8: Synthesis of compound 1-(2S,4S)-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride

[0762] Palladium on carbon (34 mg, 10% Pd, 55% H2O) was added to 1-(2S,4S)-2-(azidomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone (165 mg, 0.43 mmol) in methanol (5 mL). The mixture was stirred at room temperature for 2 hours. A solution of hydrogen chloride in dioxane (0.5 mL, 2.00 mmol, 4 mol / L) was then injected. The reaction mixture was filtered through celite to remove the palladium on carbon and concentrated under reduced pressure to yield a yellow viscous liquid (169 mg, 100% yield).

[0763] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.15–7.03 (m, 2H), 6.96–6.88 (m, 1H), 6.72 (t, J = 75.7 Hz,1H),4.54–4.44(m,1H),4.09–3.97(m,1H),3.95–3.90(m,2H),3.77–3.72(m,1H) ,3.69–3.64(m,2H),3.59–3.53(m,1H),2.35–2.22(m,1H),2.23–2.15(m,1H),2.12 (s,2.2H),2.04(s,0.8H),1.31–1.26(m,1H),0.66–0.59(m,2H),0.40–0.34(m,2H).

[0764] MS-ESI: m / z 355.25 [M-HCl+H] + .

[0765] Step 9: Compound N 2 -(((2S,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -Methyl N 5 Synthesis of 2,5-ethylpyridine dicarboxamide

[0766] The compound 1-(2S,4S)-2-aminomethyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride (163 mg, 0.42 mmol), 5-(ethyl(methyl)carbamoyl)picolinic acid (94 mg, 0.45 mmol) and 1-hydroxybenzotriazole (85 mg, 0.62 mmol) were dissolved in N,N-dimethylformamide (5 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118 mg, 0.62 mmol) and N-methylmorpholine (92 uL, 0.82 mmol) were added in an ice bath and stirred at room temperature for 15 h. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: PE / AcOEt (v / v) = 3 / 2) to give a white solid (110 mg, yield 48.43%).

[0767] 1H NMR (400MHz, CDCl3) δ (ppm): 8.81–8.71 (m, 1H), 8.65–8.56 (m, 1H), 8.19 (d, J = 8.1Hz, 1H), 7.85 (t, J = 7.4Hz, 1H), 7.09 (d, J = 8. 0Hz,1H),6.82–6.76(m,2H),6.58(t,J=75.6Hz,1H),4.55–4.46(m,1H),3.95–3.87(m,1H),3.85(d,J=6.8Hz,2H),3.82–3.74( m,1H),3.72–3.50(m,3H),3.41(t,J=9.9Hz,1H),3.33–3.21(m,1H),3.09(s,1.6H),2.94(s,1.4H),2.25–2.17(m,1H),2.19–2 .11(m,1H),2.08(s,3H),1.32–1.22(m,1H),1.24–1.21(m,1.5H),1.18–1.11(m,1.5H),0.67–0.59(m,2H),0.39–0.29(m,2H).

[0768] MS-ESI: m / z 545.30[M+H] + .

[0769] Example 43: N 2 -(((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)pyridine-2,5-dicarboxamide

[0770]

[0771] Step 1: Synthesis of 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate

[0772] The compound 1-((2R,4S)-2-(aminomethyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride (1.19 g, 3.05 mmol, Example 39, Step 9) was dissolved in dichloromethane (24 mL) solvent, and 5-(methoxycarbonyl)picolinic acid (853 mg, 4.57 mmol) and 1-hydroxy-7-azabenzotriazole (HOAT) (630 mg, 4.63 mmol) were added. The mixture was cooled at 0°C, and 1-(3-dimethylamino)-4-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-1-yl)ethanone hydrochloride was added. The mixture was stirred at room temperature for 2 h, and water (20 mL) was added to stop the reaction. The mixture was extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: methanol / dichloromethane (v / v) = 1 / 10) to give a white foam (1.01 g, yield 65.90%).

[0773] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.22 (s, 1H), 9.13 (br.s, 1H), 8.44 (dd, J = 8.1, 1.7Hz, 1H), 8.25 (d, J = 8.1Hz, 1H), 7.0 9(d,J=8.0Hz,1H),6.78(s,1H),6.77(d,J=7.5Hz,1H),6.59(t,J=75.4Hz,1H),4.35–4.27(m,1H),4.07–4.00(m,1H ),3.98(s,3H),3.96–3.89(m,1H),3.82(d,J=6.9Hz,2H),3.67–3.58(m,1H),3.43(t,J=10.8Hz,1H),3.31–3.20(m ,1H),2.63–2.54(m,1H),2.16(s,3H),2.00–1.90(m,1H),1.23–1.32(m,1H),0.67–0.62(m,2H),0.37–0.33(m,2H).

[0774] MS-ESI: m / z 518.15[M+H] + .

[0775] Step 2: Synthesis of 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinic acid

[0776] Compound 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinate (1.01 g, 1.96 mmol) was dissolved in tetrahydrofuran (20 mL). Lithium hydroxide monohydrate (440 mg, 10.49 mmol) and an aqueous solution (10 mL) were added. The mixture was stirred at 50°C for 2 h, then cooled to 0°C. 1 mol / L hydrochloric acid was added dropwise until the mixture became acidic (pH = 3). The mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate for 30 min and concentrated under reduced pressure to obtain a white solid (943 mg, 95.80% yield).

[0777] 1 H NMR (400MHz, Chloroform-d) δ (ppm): 9.77 (br.s, 1H), 9.51 (s, 1H), 8.48 (dd, J = 8.1, 2.0Hz, 1H), 8. 24(d,J=8.1Hz,1H),7.15(d,J=8.7Hz,1H),6.86–6.79(m,2H),6.62(t,J=75.5Hz,1H),4.54–4.47( m,1H),4.06–3.96(m,2H),3.88(d,J=6.9Hz,2H),3.56–3.42(m,2H),3.36–3.25(m,1H),2.75–2.65 (m,1H),2.37(s,3H),1.93–1.83(m,1H),1.35–1.23(m,1H),0.69–0.65(m,2H),0.39–0.35(m,2H).

[0778] MS-ESI: m / z 504.20[M+H] + .

[0779] Step 3: N 2 Synthesis of -((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)pyridine-2,5-dicarboxamide

[0780] Compound 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinic acid (300 mg, 0.60 mmol), ethylamine (286 mg, 3.51 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (123 mg, 0.90 mmol) were dissolved in dry tetrahydrofuran (20 mL) solvent, cooled at 0°C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added. Amine (EDCI) (440 mg, 2.30 mmol), N,N-diisopropylethylamine (DIPEA) (740 mg, 5.73 mmol), transferred to room temperature and stirred for 6 h, the reaction was stopped, and the reaction solution was concentrated under reduced pressure. Water (20 mL) was added and extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: methanol / dichloromethane (v / v) = 1 / 10) to give a white solid (300 mg, yield 90.45%).

[0781] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.16 (br.s, 1H), 9.05 (s, 1H), 8.34–8.20 (m, 2H), 7.10 (d, J = 8.0Hz, 1H), 6. 79(s,1H),6.78(d,J=9.1Hz,1H),6.59(t,J=75.5Hz,1H),4.37–4.26(m,1H),4.05–3.96(m,1H),3.93(t, J=8.8Hz,1H),3.84(d,J=6.9Hz,2H),3.64–3.56(m,1H),3.43(t,J=10.8Hz,1H),3.31–3.21(m,1H),2.64 –2.55(m,1H),2.16(s,3H),1.98–1.89(m,1H),1.33–1.21(m,1H),0.67–0.62(m,2H),0.37–0.33(m,2H).

[0782] MS-ESI: m / z 503.30 [M+H] + .

[0783] Example 44: N 2 -(((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -Methylpyridine-2,5-dicarboxamide

[0784]

[0785] Compound 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinic acid (300 mg, 0.60 mmol), methylammonium hydrochloride (270 mg, 4.00 mmol), and 1-hydroxy-7-azabenzotriazole (HOAT) (123 mg, 0.90 mmol) were dissolved in dry tetrahydrofuran (20 mL) solvent, transferred to 0°C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (360 mg, 1.88 mmol) and N,N-diisopropylethylamine (DIPEA) (769 mg, 5.59 mmol) were added, and the reaction was stirred at room temperature for 6 h. The reaction was stopped, and the reaction solution was concentrated under reduced pressure, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: methanol / dichloromethane (v / v = 1 / 10) to give a white solid product (300 mg, yield 94.15%).

[0786] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.11 (br.s, 1H), 8.98 (s, 1H), 8.22 (s, 2H), 7.09 (d, J = 7.9Hz, 1H), 6.78 (d, J = 8. 5Hz,2H),6.59(t,J=75.5Hz,1H),6.41(br.s,1H),4.34–4.26(m,1H),4.05–3.97(m,1H),3.96–3.89(m,1H), 3.83(d,J=6.9Hz,2H),3.64–3.56(m,1H),3.43(t,J=10.8Hz,1H),3.31–3.20(m,1H),3.05(d,J=4.8Hz,3H), 2.63–2.54(m,1H),2.16(s,3H),1.98–1.90(m,1H),1.31–1.22(m,1H),0.67–0.62(m,2H),0.36–0.32(m,2H).

[0787] MS-ESI: m / z 517.53[M+H] + .

[0788] Example 45: N 2 -(((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxyl-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5-ethylpyridine-2,5-dicarboxamide

[0789]

[0790] Compound 6-((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)carbamoyl)nicotinic acid (300 mg, 0.60 mmol), ethylamine (286 mg, 3.51 mmol), and 1-hydroxy-7-azabenzotriazole (HOAT) (123 mg, 0.90 mmol) were dissolved in dry DMF (20 mL) solvent, transferred to 0 ° C, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (440 mg, 2.30 mmol) and N,N-diisopropylethylamine (DIPEA) (740 mg, 5.73 mmol) were added, and the reaction was stirred at room temperature for 6 h. The reaction was stopped, and the reaction solution was concentrated under reduced pressure, diluted with water (20 mL), and extracted with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: methanol / dichloromethane (v / v) = 1 / 10) to give a white solid product (300 mg, yield 90.45%).

[0791] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.11 (br.s, 1H), 8.98 (s, 1H), 8.21 (s, 2H), 7.09 (d, J = 8.0Hz, 1H), 6.78 (d, J = 8.5Hz, 2H),6.59(t,J=75.6Hz,1H),6.35(br.s,1H),4.35–4.27(m,1H),4.05–3.96(m,1H),3.96–3.89(m,1H),3.83(d,J =6.9Hz,2H),3.64–3.57(m,1H),3.57–3.49(m,2H),3.43(t,J=10.8Hz,1H),3.31–3.20(m,1H),2.63–2.54(m,1H) ,2.16(s,3H),1.98–1.90(m,1H),1.31–1.22(m,1H),1.28(d,J=7.3Hz,3H),0.67–0.58(m,2H),0.40–0.32(m,2H).

[0792] MS-ESI: m / z 531.30 [M+H] + .

[0793] Example 46: N 2-(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Methylpyridine-2,5-dicarboxamide

[0794]

[0795] Compound N 2 -((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 2-Methylpyridine-2,5-dicarboxamide (125 mg, 0.23 mmol, Example 39) was dissolved in acetonitrile (3 mL) and concentrated hydrochloric acid (1.2 g, 32.91 mmol) was added dropwise. The mixture was stirred at 80°C for 6 h. After cooling to room temperature, the precipitate was dissolved in water and extracted with ethyl acetate (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 16:1) to obtain a white solid (74 mg, 63.30% yield).

[0796] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.11 (s, 1H), 8.64 (s, 1H), 8.21 (d, J = 8.0Hz, 1H), 7.87 (br.s, 1H), 7.04 ( d,J=8.3Hz,1H),6.88(s,1H),6.71(d,J=7.6Hz,1H),6.53(t,J=70.3Hz,1H),4.34–4.26(m,1H),4.06 –3.98(m,1H),3.95–3.88(m,1H),3.66–3.56(m,2H),3.41(t,J=10.7Hz,1H),3.31–3.19(m,2H),3.11 (s,1.7H),2.95(s,1.3H),2.60–2.51(m,1H),2.16(s,3H),1.88–1.83(m,1H),1.16(t,J=7.1Hz,3H).

[0797] MS-ESI: m / z 491.15[M+H] + .

[0798] Example 47: N 2 -(((2R,4S)-1--4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)-N5 -ethyl-N 5 -Methylpyridine-2,5-dicarboxamide

[0799]

[0800] Step 1: Compound N 2 -((((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Synthesis of methylpyridine-2,5-dicarboxamide (1245-1)

[0801] Compound N 2 -((((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 2-Methylpyridine-2,5-dicarboxamide (400 mg, 0.73 mmol) was dissolved in acetonitrile (6 mL), and concentrated hydrochloric acid (3 mL, 36.5%) was added. The mixture was heated at 80°C for 12 h. After the reaction was completed, 30 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the solvent was removed. The product was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain a white solid (180 mg, 51% yield).

[0802] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.13–9.09 (m, 1H), 8.64 (s, 1H), 8.21 (d, J = 8.0Hz, 1H), 7.90–7.83 (m, 1H), 7 .04(d,J=8.3Hz,1H),6.89–6.87(m,1H),6.72–6.70(m,1H),6.53(t,J=78.3Hz,1H),6.39(s,1H),4.29(s, 1H),4.06–4.00(m,1H),3.93–3.89(m,1H),3.66–3.54(m,2H),3.41(t,J=10.7Hz,1H),3.28–3.20(m,2H), 3.10(s,1.5H),2.95(s,1.5H),2.59–2.53(m,1H),2.15(s,3H),1.96–1.87(m,1H),1.26(t,J=7.1Hz,3H).

[0803] MS-ESI: m / z 491.20[M+H] +.

[0804] Step 2: N 2 -((((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 -Synthesis of methylpyridine-2,5-dicarboxamide (DLR011245)

[0805] Compound N 2 -((((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)-N 5 -ethyl-N 5 2-Methylpyridine-2,5-dicarboxamide (180 mg, 0.37 mmol) and 2-iodopropane (94 mg, 0.55 mmol) were dissolved in DMF (10 mL), and potassium carbonate (150 mg, 1.11 mmol) was added. The mixture was heated at 80°C for 4 h. After the reaction, 50 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the solvent was removed. The product was separated and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to obtain 130 mg of a white solid with a yield of 66%.

[0806] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.10 (s, 1H), 8.65 (s, 1H), 8.22 (d, J = 7.9Hz, 1H), 7.87 (s, 1H), 7.09 (d, J = 8.1Hz, 1H), 6.8 1(s,1H),6.77(d,J=8.2Hz,1H),6.52(t,J=75.5Hz,1H),4.57–4.44(m,1H),4.35–4.25(m,1H),4.07–4.00(m,1H),3.95 –3.91(m,1H),3.61(d,J=7.7Hz,2H),3.42(t,J=10.7Hz,1H),3.30–3.21(m,2H),3.10(s,2H),2.95(s,1H),2.62–2.55( m,1H),2.16(s,3H),1.94(dd,J=22.3,12.0Hz,1H),1.33(dd,J=5.8,2.5Hz,6H),1.29–1.22(m,1H),1.10–1.20(m,2H).

[0807] MS-ESI: m / z 533.20[M+H] + .

[0808] Example 48: N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)-N 5 -ethylpyridine-2,5-dicarboxamide

[0809]

[0810] Step 1: N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)-N 5 Synthesis of 2,5-ethylpyridine dicarboxamide

[0811] Compound N 2 -(((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 2-Ethylpyridine-2,5-dicarboxamide (150 mg, 0.28 mmol, Example 45) was dissolved in acetonitrile (5 mL) and concentrated hydrochloric acid (1 mL) was added dropwise. The mixture was stirred at 80°C for 8 h. The reaction was stopped, cooled to room temperature, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate for 30 min. Concentration under reduced pressure afforded a white solid (114 mg, 85.45% yield).

[0812] 1 H NMR (400MHz, CD3OD) δ (ppm): 9.05 (s, 1H), 8.35–8.32 (m, 1H), 8.17 (d, J = 8.1Hz, 1H), 7.04 (d, J=8.3Hz,1H),6.90–6.89(m,1H),6.80–6.78(m,1H),6.71(t,J=75.2Hz,1H),4.44–4.31(m,2H ),4.06–4.01(m,1H),3.92–3.88(m,1H),3.75–3.68(m,1H),3.49–3.42(m,3H),3.28–3.07(m ,1H),2.60–2.53(m,1H),2.26(s,1H),2.17(s,2H),1.97–1.92(m,1H),1.26(t,J=7.3Hz,3H).

[0813] MS-ESI: m / z 477.20[M+H] + .

[0814] Step 2: N2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-(isopropoxyphenyl)pyrrolidin-2-yl)methyl)-N 5 Synthesis of 2,5-ethylpyridine dicarboxamide

[0815] Compound N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)-N 5 1-Ethylpyridine-2,5-dicarboxamide (108 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (95 mg, 0.69 mmol) and 2-iodopropane (59 mg, 0.35 mmol) were added. The mixture was stirred at 80°C for 4.5 hours. The reaction was stopped, cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate for 30 minutes, and purified by silica gel column chromatography (eluent: methanol / dichloromethane (v / v) = 25%) to obtain a light brown solid (100 mg, 80.69% yield).

[0816] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.14 (s, 1H), 8.98 (s, 1H), 8.22 (s, 2H), 7.09 (d, J = 8.3Hz, 1H), 6.81 (s, 1H),6.77(d,J=8.2Hz,1H),6.53(t,J=75.6Hz,1H),6.50(br.s,1H),4.58–4.43(m,1H),4.37–4.25(m ,1H),4.06–3.97(m,1H),3.97–3.87(m,1H),3.65–3.47(m,3H),3.43(t,J=10.8Hz,1H),3.31–3.19( m,1H),2.64–2.54(m,1H),2.16(s,3H),2.02–1.88(m,1H),1.40–1.29(m,6H),1.27(d,J=7.0Hz,3H).

[0817] MS-ESI: m / z 519.20 [M+H] + .

[0818] Example 49: N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)-N 5 -Methylpyridine-2,5-dicarboxamide

[0819]

[0820] Step 1: N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)-N 5 -Synthesis of methylpyridine-2,5-dicarboxamide

[0821] Compound N 2 -(((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)-N 5 2-Methylpyridine-2,5-dicarboxamide (450 mg, 0.87 mmol, Example 44) was dissolved in acetonitrile (10 mL), and concentrated hydrochloric acid (1 mL) was added dropwise. The mixture was stirred at 80°C for 6.5 h. The reaction was stopped. After cooling to room temperature, 50 mL of water was added and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate for 30 min. The crude product was purified by silica gel column chromatography (eluent: methanol / dichloromethane (v / v) = 1 / 10) to obtain a white solid (285 mg, 70.84% ​​yield).

[0822] 1 H NMR (400MHz, CD3OD) δ (ppm): 9.06 (s, 1H), 8.34 (dd, J = 8.1, 1.8Hz, 1H), 8.18 (d, J = 8.1 Hz,1H),7.05(d,J=8.2Hz,1H),6.90(s,1H),6.79(d,J=8.2Hz,1H),6.72(t,J=75.0Hz ,1H),4.45–4.34(m,2H),4.06–4.02(m,1H),3.93–3.88(m,1H),3.77–3.68(m,1H),3. 45(t,J=10.9Hz,1H),2.98(s,3H),2.61–2.54(m,1H),2.17(s,3H),2.01–1.93(m,1H).

[0823] MS-ESI: m / z 463.20[M+H] + .

[0824] Step 2: N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)-N 5 -Synthesis of methylpyridine-2,5-dicarboxamide

[0825] Compound N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-hydroxyphenyl)pyrrolidin-2-yl)methyl)-N 5 -Methylpyridine-2,5-dicarboxamide (140 mg, 0.3 mmol) was dissolved in 10 mL of N,N-dicarboxamide solvent, and then anhydrous potassium carbonate (120 mg, 0.9 mmol) and 2-iodopropane (76 mg, 0.45 mmol) were added. The mixture was stirred at 80 ° C for 4 h, the reaction was stopped, and the mixture was cooled to room temperature. Water (50 mL) was added and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate for 30 min. The organic phases were chromatographed on a silica gel column (eluent: methanol / dichloromethane (v / v) = 25%) to give a light brown solid (91 mg, yield 59.86%).

[0826] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.13 (s, 1H), 8.98 (s, 1H), 8.22 (s, 2H), 7.09 (d, J = 7.6Hz, 1 H),6.81–6.70(m,2H),6.70(s,1H),6.53(t,J=75.5Hz,1H),4.58–4.41(m,1H),4.36–4. 24(m,1H),4.07–3.86(m,2H),3.67–3.52(m,1H),3.43(t,J=10.3Hz,1H),3.32–3.19(m, 1H),3.04(s,3H),2.64–2.53(m,1H),2.16(s,3H),2.03–1.84(m,1H),1.37–1.26(m,6H).

[0827] MS-ESI: m / z 505.20[M+H] + .

[0828] Example 50: N 2 -(((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl)pyridine-2,5-dicarboxamide

[0829]

[0830] Compound 1-((2R,4S)-2-(aminomethyl)-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-1-yl)ethanone hydrochloride (100 mg, 0.26 mmol, Example 58 Step 11), 5-carbamoylpicolinic acid (45 mg, 0.26 mmol) and 1-hydroxy-7-azabenzotriazole (71 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (10 mL) solution, and 1-(3-dimethylformamide) was added in sequence under ice-cooling. Aminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol) were reacted at room temperature for 10 h. After the reaction of the raw materials was complete, the reaction was stopped and saturated brine (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to give a white solid (78 mg, yield 61%).

[0831] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.17 (s, 1H), 9.07 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.09 (d, J =8.1Hz,1H),6.81(s,1H),6.77(d,J=7.8Hz,1H),6.52(t,J=75.5Hz,1H),6.18(s,1H),4.54 –4.46(m,1H),4.31(s,1H),4.03–3.91(m,2H),3.66–3.56(m,1H),3.43(t,J=10.4Hz,1H),3 .33–3.19(m,1H),2.65–2.55(m,1H),2.15(s,3H),1.97–1.87(m,1H),1.32(d,J=3.9Hz,6H).

[0832] MS-ESI: m / z 491.20[M+H] + .

[0833] Example 51: ((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate

[0834]

[0835] Step 1: Synthesis of ((2R,4S)-1-(tert-Butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate

[0836] The compound (2R, 4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (380 mg, 0.92 mmol, Example 39, Step 4) was dissolved in N,N-dimethylformamide (10 mL) solvent, and 5-(ethyl(methyl)carbamoyl)picolinic acid (211 mg, 1.01 mmol) and 1-hydroxybenzotriazole (HOBT) (249 mg, 1.84 mmol) were added. The mixture was cooled at 0°C, and 1-(3-difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid was added. (Methylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (353 g, 1.84 mmol), N-methylmorpholine (NMM) (279 mg, 2.76 mmol), transferred to room temperature and stirred for 16 h, water (20 mL) was added to stop the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA (v / v) = 1 / 3) to give a colorless oily product (287 mg, yield 51.68%).

[0837] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.77 (s, 1H), 8.19–8.10 (m, 1H), 7.93–7.84 (m, 1H), 7.12–7.05 (m, 1H), 6.89 –6.80(m,2H),6.58(t,J=75.7Hz,1H),4.77–4.53(m,2H),4.42–4.21(m,1H),4.20–3.92(m,1H),3.84(d,J =6.9Hz,2H),3.69–3.55(m,1H),3.35–3.16(m,3H),3.10(s,1.7H),2.95(s,1.3H),2.64-2.52(m,1H),2.1 7–1.93(m,1H),1.62(s,3H),1.56–1.36(m,9H),1.17–1.14(m,1H),0.67–0.58(m,2H),0.37–0.29(m,2H).

[0838] MS-ESI: m / z 604.30[M+H] + .

[0839] Step 2: Synthesis of ((2R,4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate hydrochloride

[0840] The compound ((2R,4S)-1-(tert-butoxycarbonyl)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate (290 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL) solvent, and a solution of hydrochloric acid in 1,4-dioxane (2.4 mL, 9.60 mmol) was added. The reaction was stirred at room temperature for 2 h, the reaction was stopped, and the mixture was concentrated under reduced pressure once. Then, dichloromethane (20 mL) was added to dissolve it, and it was concentrated under reduced pressure again to give a white solid product (241 mg, 92.97%).

[0841] 1 H NMR(400MHz,CD3OD)δ(ppm):8.86–8.79(m,1H),8.43–8.34(m,1H),8.26–8.13(m,1H),7.19–7.09(m,2H),7 .03–6.95(m,1H),6.75(t,J=75.6Hz,1H),4.85–4.77(m,1H),4.74–4.63(m,1H),4.31–4.20(m,1H),3.93(d ,J=6.9Hz,2H),3.86–3.78(m,1H),3.77–3.57(m,3H),3.50–3.39(m,1H),3.13(s,2H),3.01(s,2H),2.69–2 .59(m,1H),2.18–2.04(m,1H),1.41–1.22(m,3H),1.21–1.16(m,1H),0.68–0.59(m,2H),0.41–0.33(m,2H).

[0842] MS-ESI: m / z 504.30 [M-HCl+H] + .

[0843] Step 3: Synthesis of ((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate

[0844] The compound ((2R,4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate hydrochloride (241 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL) solvent and cooled at 0°C. N,N-diisopropylethylamine (DIPEA) (248 mg, 1.92 mmol) and acetyl chloride (75 mg, 0.96 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction solution was washed with water (20 mL×2) and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a light yellow solid product (108 mg, yield 41.24%).

[0845] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.77 (s, 1H), 8.16 (d, J = 8.0Hz, 1H), 7.92–7.83 (m, 1H), 7.14–7.05 (m, 1H), 6.94–6.82 (m ,2H),6.59(t,J=75.6Hz,1H),4.82–4.74(m,1H),4.73–4.64(m,1H),4.63–4.51(m,1H),3.94–3.88(m,1H),3.88–3.80 (m,2H),3.66–3.56(m,1H),3.51(t,J=10.8Hz,1H),3.33–3.22(m,2H),3.11(s,1.7H),2.96(s,1.3H),2.64–2.54(m,1 H),2.24(s,0.6H),2.15–2.02(m,3.4H),1.34–1.21(m,3H),1.18–1.13(m,1H),0.68–0.56(m,2H),0.38–0.28(m,2H).

[0846] MS-ESI: m / z 546.20[M+H] + .

[0847] Example 52: ((2R,4S)-1-Acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(ethylcarboxamido)picolinate

[0848]

[0849] Step 1: Synthesis of 6-(methoxycarbonyl)nicotinic acid

[0850] Pyridine-2,5-dicarboxylic acid (500 mg, 2.99 mmol) was added to methanol (10 mL), and concentrated sulfuric acid (0.16 mL, 2.99 mmol) was slowly added. The reaction was refluxed at 70°C for 1 h, cooled to room temperature, and ice water (20 mL) was added. The mixture was stirred until a white solid was completely precipitated, then filtered and the solid was dissolved in tetrahydrofuran (20 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a white solid product (400 mg, yield 73.85%).

[0851] 1 H NMR(400MHz, DMSO-d6)δ(ppm):9.20–9.11(m,1H),8.49–8.39(m,1H),8.22–8.09(m,1H),3.91(s,3H).

[0852] MS-ESI: m / z 182.10[M+H] + .

[0853] Step 2: Synthesis of methyl 5-(ethylcarbamoyl)picolinate

[0854] Compound 6-(methoxycarbonyl)nicotinic acid (2.50 g, 13.80 mmol), ethylamine hydrochloride (1.35 g, 16.56 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (3.76 g, 27.60 mmol) were dissolved in dry N,N-dimethylformamide (30 mL) solvent, cooled at 0 ° C, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (5.29 g, 27.60 mmol), N,N-diisopropylethylamine (DIPEA) (5.35 g, 41.40 mmol), transferred to room temperature and stirred for 27 h, the reaction was stopped, the solvent was concentrated under reduced pressure, water (30 mL) was added to dissolve the concentrate, and the extract was extracted with dichloromethane (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a white solid (1.78 g, yield 61.95%).

[0855] 1 H NMR (400MHz, MeOH-d4) δ (ppm): 9.07–9.02 (m, 1H), 8.39–8.32 (m, 1H), 8.25–8.19 (m, 1H), 4.00 (s, 3H), 3.51–3.42 (m, 2H), 1.25 (t, J = 7.3Hz, 3H).

[0856] MS-ESI: m / z 209.10[M+H] + .

[0857] Step 3: Lithium 5-(ethylcarbamoyl)picolinate

[0858] The compound 5-(ethylcarbamoyl)picolinic acid methyl ester (1.77 g, 8.50 mmol) was dissolved in tetrahydrofuran (16 mL) solvent, and lithium hydroxide monohydrate (0.37 g, 8.93 mmol) and aqueous solution (2.5 mL) were added. The mixture was stirred at 50 ° C for 23 h, cooled to room temperature and filtered, and the filter cake was vacuum dried at 50 ° C for 8 h to obtain a white solid product (1.55 g, yield 91.12%).

[0859] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.89–8.84 (m, 1H), 8.33–8.23 (m, 1H), 8.02 (d, J = 8.1Hz, 1H), 3.34–3.26 (m, 2H), 1.14 (t, J = 7.2Hz, 3H).

[0860] MS-ESI: m / z 195.20[M-Li+2H] + .

[0861] Step 4: Synthesis of ((2R,2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methanol hydrochloride

[0862] The compound tert-butyl (2R,2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.7 g, 4.11 mmol, Step 4 of Example 39) was dissolved in dichloromethane (15 mL) and a solution of hydrochloric acid in 1,4-dioxane (10.3 mL, 41.1 mmol) was added. The reaction was stirred at room temperature for 2 h, the reaction was stopped, and the mixture was concentrated under reduced pressure once. Then, dichloromethane (20 mL) was added to dissolve the mixture and the mixture was concentrated under reduced pressure again to obtain a light brown oily product (1.44 g, 100% yield).

[0863] 1H NMR (400MHz, CDCl3) δ (ppm): 7.11 (d, J = 8.1Hz, 1H), 6.89 (s, 1H), 6.83 (d, J = 8.2Hz, 1H), 6.60(t,J=75.5Hz,1H),4.74(br.s,1H),4.11–4.03(m,1H),4.02–3.91(m,2H),3.89–3. 81(m,2H),3.76(s,1H),3.62–3.48(m,1H),3.40–3.24(m,1H),2.44–2.32(m,1H),2.17( br.s,1H),2.08–1.96(m,1H),1.32–1.25(m,1H),0.67–0.59(m,2H),0.40–0.31(m,2H).

[0864] MS-ESI: m / z 314.20[M+H] + .

[0865] Step 5: Synthesis of methyl ((2R,2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetate

[0866] The compound ((2R,2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methanol hydrochloride (1.44 g, 4.12 mmol) was dissolved in dichloromethane (20 mL) solvent and cooled at 0°C. N,N-diisopropylethylamine (DIPEA) (2.66 g, 20.6 mmol) and acetyl chloride (0.97 g, 12.36 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction solution was washed with water (20 mL × 2) and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EA / PE (v / v) = 9 / 1) to give a yellow liquid product (1.15 g, yield 70.24%).

[0867] 1H NMR(400MHz, CDCl3)δ(ppm):7.16–7.08(m,1H),6.87–6.76(m,2H),6.80–6. 39(m,1H),4.39(s,2H),4.29–4.18(m,1H),3.96–3.78(m,3H),3.45–3.33(m, 1H),3.33–3.13(m,1H),2.55–2.45(m,1H),2.17(s,1H),2.13–2.05(m,5H), 2.01–1.87(m,1H),1.33–1.26(m,1H),0.73–0.60(m,2H),0.43–0.29(m,2H).

[0868] MS-ESI: m / z 398.20[M+H] + .

[0869] Step 6: Synthesis of 1-((2R,2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethyl-1-one

[0870] Methyl ((2R,2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)acetate (1.15 g, 2.89 mmol) was dissolved in tetrahydrofuran (20 mL). Lithium hydroxide monohydrate (0.30 g, 7.23 mmol) and an aqueous solution (10 mL) were added. The mixture was stirred at 50°C for 2 h, then cooled to 0°C. 1M hydrochloric acid was added dropwise until the mixture became acidic (pH = 2). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily product (1.00 g, 97.37% yield).

[0871] 1H NMR (400MHz, CDCl3) δ (ppm): 7.14–7.09 (m, 1H), 6.81–6.78 (m, 2H), 6.60 (t, J = 73.8Hz ,1H),4.27–4.18(m,1H),3.95–3.89(m,1H),3.89–3.83(m,2H),3.82–3.74(m,1H),3. 70–3.63(m,1H),3.47–3.37(m,1H),3.34–3.23(m,1H),2.48–2.40(m,1H),2.16–2.10 (m,3H),1.74–1.60(m,1H),1.34–1.27(m,1H),0.69–0.62(m,2H),0.39–0.32(m,2H).

[0872] MS-ESI: m / z 356.15[M+H] + .

[0873] Step 7: Synthesis of methyl ((2R,2S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)5-(ethylcarbamoyl)picolinate

[0874] Lithium 5-(ethylcarbamoyl)picolinate (168 mg, 0.84 mmol) and a solution of hydrochloric acid in 1,4-dioxane (0.28 mL, 1 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred until clear. 1-((2R,2S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethyl-1-one (11250-3) (200 mg, 0.56 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (114 mg, 0.84 mmol) were added. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (268 mg, 1.40 mmol) and N,N-diisopropylethylamine (DIPEA) (325 mg, 2.52 mmol) were added in sequence under ice bath, and the reaction was stirred at room temperature for 9 h. Water (20 mL) was added and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and washed with saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated and mixed, and the product was purified by column chromatography (DCM / MeOH (v / v) = 15 / 1) to give a white solid product (151 mg, yield 50.73%).

[0875] 1H NMR (400MHz, CDCl3) δ (ppm): 9.05 (s, 1H), 8.28–8.19 (m, 1H), 8.19–8.11 (m, 1H), 7.14–7.05 (m, 1H), 6.91–6.82(m,2H),6.80–6.35(m,1H),6.40(s,1H),4.82–4.72(m,1H),4.71–4.62(m,1H),4.62–4.5 3(m,1H),3.94–3.87(m,1H),3.85–3.74(m,2H),3.61–3.45(m,3H),3.36–3.22(m,1H),2.65–2.52(m ,1H),2.23(s,0.6H),2.15–2.01(m,3.4H),1.34–1.21(m,4H),0.69–0.53(m,2H),0.39–0.21(m,2H).

[0876] MS-ESI: m / z 532.20[M+H] + .

[0877] Example 53: ((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-(methylcarbamoyl)picolinate

[0878]

[0879] Step 1: Synthesis of methyl 5-(methylcarbamoyl)picolinate

[0880] Compound 6-(methoxycarbonyl)nicotinic acid (2.35 g, 12.97 mmol, Example 52, Step 1), methylamine hydrochloride (1.05 g, 15.56 mmol), and 1-hydroxy-7-azabenzotriazole (HOAT) (3.76 g, 27.60 mmol) were dissolved in dry N,N-dimethylformamide (30 mL) and cooled at 0°C. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (4.97 g, The mixture was stirred at room temperature for 17 h, the reaction was stopped, the solvent was concentrated under reduced pressure, and water (30 mL) was added to dissolve the concentrate, which was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a white solid (1.50 g, yield 59.56%).

[0881] 1H NMR (400MHz, CD3OD) δ (ppm): 9.10–9.00 (m, 1H), 8.42–8.32 (m, 1H), 8.28–8.19 (m, 1H), 4.00 (s, 3H), 2.96 (s, 3H).

[0882] MS-ESI: m / z 195.10 [M+H] + .

[0883] Step 2: Synthesis of lithium 5-(methylcarbamoyl)picolinate

[0884] Compound 5-(ethylcarbamoyl)picolinic acid methyl ester (250-1) (1.40 g, 7.21 mmol) was dissolved in tetrahydrofuran (16 mL) solvent, and lithium hydroxide monohydrate (0.36 g, 8.65 mmol) and aqueous solution (2.5 mL) were added. The mixture was stirred at 50°C for 23 h, and the reaction solution was concentrated and dried in vacuo at 50°C for 8 h to obtain a white solid product (1.40 g, 100% yield).

[0885] 1 H NMR (400MHz, CD3OD) δ (ppm): 8.99–8.94 (m, 1H), 8.28–8.22 (m, 1H), 8.12–8.06 (m, 1H), 2.95 (s, 3H).

[0886] MS-ESI: m / z 181.20[M-Li+2H] + .

[0887] Step 3: Synthesis of ((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl) 5-(methylcarbamoyl)picolinate

[0888] A solution of 5-(methylcarbamoyl)picolinate lithium (248 mg, 1.33 mmol) and hydrochloric acid in 1,4-dioxane (0.45 mL, 1.78 mmol) was dissolved in N,N-dimethylformamide (6 mL). After stirring until clear, 1-((2R,4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethyl-1-one (315 mg, 0.89 mmol, Example 52, Step 6), 1-hydroxy-7-azabenzotriazole (HOAT) (182 mg, 1.33 mmol) were added. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (426 mg, 2.23 mmol) and N,N-diisopropylethylamine (DIPEA) (517 mg, 4.00 mmol) were added in sequence under ice bath, and the mixture was stirred at room temperature for 24 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 2), and dried over anhydrous sodium sulfate. The organic phase was concentrated and mixed, and then purified by column chromatography (DCM / MeOH (v / v) = 15 / 1) to obtain a white solid product (206 mg, yield 44.72%).

[0889] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.06 (s, 1H), 8.30–8.21 (m, 1H), 8.20–8.10 (m, 1H), 7.09 (d, J = 8.0Hz, 1H), 6.91–6.80 (m,2H),6.67–6.61(m,1H),6.59(t,J=75.6Hz,1H),4.78–4.73(m,1H),4.70–4.63(m,1H),4.62–4.54(m,1H),3.94– 3.87(m,1H),3.81(d,J=6.9Hz,2H),3.51(t,J=10.8Hz,1H),3.35–3.24(m,1H),3.05(d,J=4.7Hz,3H),2.63–2.53( m,1H),2.22(s,0.6H),2.14–2.02(m,1H),2.09(s,2.4H),1.27–1.22(m,1H),0.67–0.57(m,2H),0.38–0.26(m,2H).

[0890] MS-ESI: m / z 518.20[M+H] + .

[0891] Example 54: ((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-carbamoylpicolinate

[0892]

[0893] Step 1: Synthesis of methyl 5-carbamoylpicolinate

[0894] Compound 6-(methoxycarbonyl)nicotinic acid (2.50 g, 13.80 mmol, Example 52 Step 1), ammonium chloride (1.11 g, 20.70 mmol), and 1-hydroxy-7-azabenzotriazole (HOAT) (3.76 g, 27.60 mmol) were dissolved in N,N-dimethylformamide (30 mL) and cooled at 0°C. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (5.29 g, 27.6 0mmol), N,N-diisopropylethylamine (DIPEA) (5.35g, 41.40mmol), transferred to room temperature and stirred for 27h, the reaction was stopped, the solvent was concentrated under reduced pressure, water (30mL) was added to dissolve the concentrate, and the extract was extracted with dichloromethane (30mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM / MeOH (v / v) = 20 / 1) to give a colorless liquid (1.26g, yield 50.68%).

[0895] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.14–9.07 (m, 1H), 8.43–8.35 (m, 1H), 8.33 (s, 1H), 8.13 (d, J = 8.1Hz, 1H), 7.78 (s, 1H), 3.90 (s, 3H).

[0896] MS-ESI: m / z 181.15[M+H] + .

[0897] Step 2: Synthesis of lithium 5-carbamoylpicolinate

[0898] Compound 5-(ethyl(methyl)carbamoyl)picolinic acid methyl ester (249-1) (1.24 g, 6.88 mmol) was dissolved in tetrahydrofuran (20 mL) solvent, and lithium hydroxide monohydrate (0.32 g, 7.57 mmol) and aqueous solution (10 mL) were added. The mixture was stirred at 50°C for 3.5 h, and then concentrated under reduced pressure to remove the solvent. The product was dried in vacuo at 50°C for 8 h to obtain a white solid product (1.18 g, yield 99.68%).

[0899] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.94–8.87 (m, 1H), 8.34–8.27 (m, 1H), 8.24 (s, 1H), 8.01 (d, J = 8.1Hz, 1H), 7.63 (s, 1H).

[0900] MS-ESI:m / z167.25[M-Li+2H] + .

[0901] Step 3: Synthesis of ((2R,4S)-1-acetyl-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pyrrolidin-2-yl)methyl 5-carbamoylpicolinic acid

[0902] Lithium 5-carbamoylpicolinate (248 mg, 1.44 mmol) and a solution of hydrochloric acid in 1,4-dioxane (0.48 mL, 1.92 mmol) were dissolved in DMF (5 mL). After stirring until clear, 1-((2R,4S)-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(hydroxymethyl)pyrrolidin-1-yl)ethyl-1-one (342 mg, 0.96 mmol, Example 52, Step 6) and 1-hydroxy-7-azabenzotriazole (HOAT) (196 mg, 1.44 mmol) were added in sequence under ice-cooling. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (460 mg, 2.40 mmol) and N,N-diisopropylethylamine (DIPEA) (558 mg, 4.32 mmol) were added, and the mixture was stirred at room temperature for 24 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 2), and dried over anhydrous sodium sulfate. The organic phase was concentrated and mixed, and then purified by silica gel column chromatography (DCM / MeOH (v / v) = 15 / 1) to obtain a white solid product (180 mg, yield 37.24%).

[0903] 1H NMR(400MHz, CDCl3)δ(ppm):9.14(s,1H),8.39–8.28(m,1H),8.24–8.12(m,1H),7.21–7.01(m,1H),6.96–6 .81(m,2H),6.76–6.63(m,1H),6.59(t,J=75.6Hz,1H),6.23–5.98(m,1H),4.82–4.73(m,1H),4.71–4.63(m, 1H),4.62–4.46(m,1H),3.98–3.86(m,1H),3.86–3.75(m,2H),3.52(t,J=10.7Hz,1H),3.37–3.21(m,1H),2 .65–2.51(m,1H),2.23(s,1H),2.15–2.02(m,3H),1.27–1.22(m,1H),0.69–0.56(m,2H),0.39–0.25(m,2H).

[0904] MS-ESI: m / z 504.20[M+H] + .

[0905] Example 55: ((2R,4S)-1-acetyl-4-(4-(difluoromethoxy)-3-isopropoxyphenyl)pyrrolidin-2-yl)methyl 5-(ethyl(methyl)carbamoyl)picolinate

[0906]

[0907] Step 1: Synthesis of 2-(difluoromethoxy)-5-iodophenol

[0908] In a 250 mL two-necked round-bottom flask, 2-(cyclopropylmethoxy)-1-(difluoromethoxy)-4-iodobenzene (20.00 g, 58.80 mmol) was added and dissolved in acetonitrile (80 mL). Concentrated hydrochloric acid (40 mL) was then slowly added dropwise. Under nitrogen protection, the mixture was reacted in an 80°C oil bath for 12 h, after which the reaction was stopped. After cooling to room temperature, water (100 mL) was added, followed by extraction with ethyl acetate (100 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate for 30 min. The crude product was purified by silica gel column chromatography (eluent: PE = 100%) to obtain a light yellow oily product (13.4 g, 79.68% yield).

[0909] 1H NMR (400MHz, CDCl3) δ (ppm): 7.37 (d, J = 2.0Hz, 1H), 7.21 (dd, J = 8.5, 2.1Hz, 1H), 6.85 (d, J = 8.5Hz, 1H), 6.51 (t, J = 73.1Hz, 1H), 5.61 (s, 1H).

[0910] GC-MS: m / z 285.9[M] + .

[0911] Step 2: Synthesis of 1-(difluoromethoxy)-4-iodo-2-isopropoxybenzene

[0912] 2-(Difluoromethoxy)-5-iodophenol (11.4 g, 39.86 mmol) was added to a 250 mL single-necked flask and dissolved in N,N-dimethylformamide (55 mL). Potassium carbonate (16.53 g, 119.58 mmol) and 2-iodopropane (10.16 g, 59.79 mmol) were then added. The mixture was stirred at 80°C for 2 h and the reaction was stopped. The mixture was cooled to room temperature, water (150 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate for 30 min, and concentrated under reduced pressure to obtain a light yellow oily product (12.51 g, yield 95.66%).

[0913] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.26–7.23 (m, 2H), 6.88 (d, J = 8.3Hz, 1H), 6.52 (t, J = 75.2Hz, 1H), 4.56-4.50 (m, 1H), 1.36 (d, J = 6.1Hz, 6H).

[0914] GC-MS: m / z 328[M] + .

[0915] Step 3: Synthesis of compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0916] The compound 1-(difluoromethoxy)-4-iodo-2-isopropoxybenzene (13.7 g, 41.76 mmol), pinacol diboron (11.13 g, 43.85 mmol), potassium acetate (6.15 g, 62.64 mmol), 2-dicyclohexylphosphino-2'-methylbiphenyl (Mephos) (1.52 g, 4.18 mmol) and palladium acetate (470 mg, 2.09 mmol) were dissolved in dry N,N-dimethylformamide (82 mL) and reacted at 80°C under nitrogen for 2 h. After the reaction solution was cooled, water (700 mL) was added and mixed, and the mixture was extracted with ethyl acetate (40 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / PE (v / v) = 1 / 10) to give a brown liquid product (11.4 g, yield 83.19%).

[0917] 1 H NMR (400MHz, CDCl3) δ (ppm): 7.40 (s, 1H), 7.39 (d, J = 9.3Hz, 1H), 7.14 (d, J = 7.8Hz, 1H), 6.60 (t, J F-H =75.5Hz,1H),4.69–4.62(m,1H),1.36(d,J=6.1Hz,6H),1.34(s,12H).

[0918] GC-MS: m / z 286.10 [M-(i-Pr)+H].

[0919] Step 4: Synthesis of (R)-1-tert-butyl 2-methyl 4-(4-(difluoromethoxy)-3-isopropoxyphenyl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate

[0920] The compound 2-(4-(difluoromethoxy)-3-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.58 g, 32.24 mmol), (R)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2-(2H,5H)-dicarboxylate (11.0 g, 29.31 mmol, intermediate M2), palladium acetate (160 mg, 0.73 mmol), 2-dicyclohexylphosphino-2'-methylbiphenyl (Mephos) (530 mg, 1.47 ...

Claims

1. A compound, which is a compound represented by formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by formula (I): (I)； in: R 1 and R 2 are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl-C 1-4 Alkylene, C 1-6 Alkyl-C(=O)-, C 3-8 Cycloalkyl-C(=O)- or heterocyclic-C(=O)- 1-4 Alkylene; X and X 1 Each independently is -O-; R 3 C 1-6 Alkyl-C(=O)- or C 1-6 Alkyl-S(=O) t -, where R 3 Unsubstituted or substituted with 1, 2, 3 or 4 R 6 replaced by; Each R 6 are independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Alkylamino; R 4 -(CH2) m -L-(CH2) n -G; L is -NR x -C(=O)-, -NR x -C(=O)-NR y -, -NR x -C(=O)-O- or -C(=O)-O-; Among them, each R x and R y are independently hydrogen, deuterium, C 1-6 Alkyl or C 1-6 Haloalkyl; G is C 3-8 Cycloalkyl, C 6-10 aryl, a heterocyclic group consisting of 3 to 10 atoms, or a heteroaryl group consisting of 5 to 10 atoms; wherein G is unsubstituted or replaced by 1, 2, 3 or 4 R 7 replaced by; Each R 7 are independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, -C(=O)-NR a R b 、-S(=O) t -NR a R b , C 1-6 Alkyl-C(=O)-N(R c )-、C 1-6 Alkyl-S(=O) t -N(R c )-、C 1-6 Alkoxy-C(=O)-N(R c )-、C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-S(=O) t -、C 1-6 Alkoxy-C(=O)- or C 1-6 Alkyl-C(=O)-O-; Each R a and R b are independently hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 6-10 aryl, a heterocyclic group consisting of 3 to 10 atoms, or a heteroaryl group consisting of 5 to 10 atoms, wherein each R a and R b are independently unsubstituted or substituted with 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O)-NH2, C 1-6 Alkoxy C(=O)-, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 substituted with an alkylamino group; Each R c are independently hydrogen, deuterium, C 1-3 Alkyl or C 1-3 Haloalkyl; R is hydrogen or deuterium; R 5a , R 5b , R 6a and R 6b each independently is hydrogen or deuterium; t is 1 or 2; n is 0, 1 or 2; m is 1 or 2.

2. The compound according to claim 1, which is a compound represented by formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by formula (II): (II)。 3. The compound according to claim 1, which is a compound represented by formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt of the compound represented by formula (III): (III)。 4. The compound according to claim 1, wherein: R 1 and R 2 and each is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, cyclopropylmethylene, cyclopropylethylidene, cyclobutylmethylene, cyclobutylethylidene, cyclopentylmethylene, cyclopentylethylidene, cyclohexylmethylene, cyclohexylethylidene, CH3C(=O)-, CH3CH2C(=O)-, CH3CH2CH2C(=O)-, (CH3)2CHC(=O)-, cyclopropyl-C(=O)-, cyclobutyl-C(=O)-, cyclopentyl-C(=O)-, cyclohexyl-C(=O)-, piperazinyl-C 1-3 Alkylene, piperidinyl-C 1-3 Alkylene, morpholinyl-C 1-3 Alkylene, thiomorpholinyl-C 1-3 Alkylene, tetrahydropyranyl-C 1-3 Alkylene or pyrrolidinyl-C 1-3 Alkylene; R 3 is CH3-C(=O)-, CH3CH2-C(=O)-, CH3CH2CH2-C(=O)-, (CH3)2CH-C(=O)-, CH3-S(=O)2-, CH3CH2-S(=O)2-, CH3CH2CH2-S(=O)2- or (CH3)2CH-S(=O)2-, wherein R 3 Unsubstituted or substituted with 1, 2, 3 or 4 R 6 replaced by; Each R 6 and -1, -2, -3, -4, -6, -7, -8, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, -24, -25, -26, -27, -28, -29, -30, -31, -32, -33, -34, -35, -36, -37, -38, -39, -40, -50, -60, -61, -62, -63, -64, -65, -66, -67, -68, -69, -70, -71, -72, -73, -74, -75 5. The compound according to claim 1, wherein: Each R x and R y are independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl or C 1-4 Halogenated alkyl.

6. The compound according to claim 1, wherein: G is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; wherein G is unsubstituted or replaced by 1, 2, 3 or 4 R 7 replaced by; Each R 7 are independently deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, carboxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, -C(=O)-NR a R b 、-S(=O)2-NR a R b , C 1-4 Alkyl-C(=O)-NH-, C 1-4 Alkyl-S(=O)2-NH-, C 1-4 Alkoxy-C(=O)-NH-, CH3-C(=O)-, CH3CH2-C(=O)-, CH3CH2CH2-C(=O)-, (CH3)2CH-C(=O)-, CH3CH2CH2 CH2-C(=O)-, CH3-S(=O)2-, CH3CH2-S(=O)2-, CH3CH2CH2-S(=O)2-, (CH3)2CH-S(=O)2-, CH3O-C(= O)-, CH3CH2O-C(=O)-, CH3CH2CH2O-C(=O)-, (CH3)2CHO-C(=O)-, CH3CH2CH2CH2O-C(=O)-, CH3-C( =O)-O-, CH3CH2-C(=O)-O-, CH3CH2CH2-C(=O)-O-, (CH3)2CH-C(=O)-O-, or CH3CH2CH2CH2-C(=O)-O-.

7. The compound according to claim 1, wherein: Each R a and R b R is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, phenyl, naphthyl, pyridyl, pyrimidyl, furanyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl or pyrrolidinyl; wherein each R a and R b are independently unsubstituted or substituted with 1, 2 or 3 groups selected from deuterium, -F, -Cl, -Br, -I, hydroxy, amino, cyano, oxo, -C(=O)-NH2, C 1-3 Alkoxy C(=O)-, C 1-3 Alkyl-C(=O)-NH-, C 1-3 Alkyl-S(=O) t -NH-, methyl, ethyl, n-propyl, isopropyl, n-butyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2Cl, -CHCl2, methoxy, ethoxy, n-propyloxy, isopropyloxy, N -Methylamino, N -Ethylamino, N'N -dimethylamino, N'N -diethylamino or N'N -methylethylamino group.

8. The compound according to claim 1, which is a compound having one of the following structures or a stereoisomer, tautomer or pharmaceutically acceptable salt of a compound having one of the following structures: (1)、 (2)、 (3)、 (4)、 (5)、 (6)、 (7)、 (8)、 (9)、 (10)、 (11)、 (12)、 (13)、 (14)、 (15)、 (16)、 (17)、 (18)、 (19)、 (20)、 (21)、 (22)、 (23)、 (24)、 (25)、 (26)、 (27)、 (28)、 (29)、 (30)、 (31)、 (32)、 (33)、 (34)、 (35)、 (36)、 (37)、 (38)、 (39)、 (40)、 (41)、 (42)、 (43)、 (44)、 (45)、 (46)、 (47)、 (48)、 (49)、 (50)、 (51)、 (52)、 (53)、 (54)、 (55)、 (56)、 (57) (58) (59) (60) (61) (62) (63) (64) (65) (66) (67) (68) (69) (70) (71) (72) or (73).

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, optionally further comprising a pharmaceutically acceptable adjuvant.

10. The pharmaceutical composition according to claim 9, further comprising 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, carmoxicilol, budesonide, beclomethasone dipropionate, triamcinolone acetonide, flunisolide, mometasone furoate, roflenide, ciclesonide, ipratropium, oxitropium, tiotropium, glycopyrrolate, umeclidinium, vilanterol, aclidinium, benralizumab, tralokinumab, revatolide, crisabor, fluocinolone acetonide, desoximetasone, mometasone, triamcinolone, betamethasone, alclometasone, desonide, hydrocortisone , clobetasol, 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, durudan Anti-, levitra, nimolizumab, tromagillinumab, 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 a combination thereof.

11. Use of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to any one of claims 9 to 10 in the preparation of a medicament, wherein the medicament is used 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 mentioned are: chronic obstructive pulmonary disease, emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchiectasis, acute respiratory distress syndrome or respiratory inflammation; The pulmonary fibrosis described herein is: pulmonary tuberculosis fibrosis or pulmonary cystic fibrosis; The inflammation described is: allergic conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis.

13. The use according to claim 12, wherein The respiratory tract inflammation is bronchitis or allergic rhinitis; wherein bronchitis is acute bronchitis, chronic bronchitis, allergic bronchitis, diffuse panbronchiolitis or obliterative bronchiolitis.

Images