3,4-dihydro-2h-benzo[b][1,4]dioxepane compound, and preparation method therefor and pharmaceutical use thereof

Abstract

The present invention relates to a 3,4-dihydro-2H-benzo[b][1,4]dioxepane compound, and a preparation method therefor and the pharmaceutical use thereof. In particular, the present invention relates to a compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof as an α4β7 integrin inhibitor. The compound and the pharmaceutical composition containing the compound can be used for treating and / or preventing diseases related to α4β7 integrin, such as inflammatory bowel disease. The definition of each group in general formula (I) is the same as defined in the description.

Description

3,4-Dihydro-2H-benzo[b][1,4]dioxepane compounds, preparation methods and medical uses thereof Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to 3,4-dihydro-2H-benzo[b][1,4]dioxepane compounds represented by general formula (I), their preparation methods and pharmaceutical compositions containing them, as well as their use as α4β7 integrin inhibitors in the treatment and / or prevention of diseases related to α4β7 integrin activity. Background Art

[0002] Integrins are non-covalent heterodimers composed of α and β subunits. Twenty-four functionally distinct integrin receptors, comprising 18 α subunits and 8 β subunits, have been discovered in mammals. As adhesion receptors, integrins regulate signaling between cells and their environment through various mechanisms, including protein-protein interactions, conformational changes, and transport, at the plasma membrane. Integrins serve as therapeutic targets for a variety of diseases, including cancer, fibrosis, cardiovascular disease, viral infection, and autoimmune disorders.

[0003] α4β7 integrin, a member of the integrin family, is a cell adhesion receptor, a heterodimer composed of two subunits, α4 and β7. α4β7 integrin is a lymphocyte homing receptor that binds to two ligands, mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) and vascular cell adhesion molecule-1 (VCAM-1), both of which are expressed in different tissues. The primary ligand for α4β7 is MAdCAM-1, which is thought to be specifically expressed on venular endothelial cells in the intestine and gut-associated lymphoid tissues, with only minimal expression in extraintestinal tissues. VCAM-1 is widely expressed on venular endothelial cells throughout the body, in peripheral lymph nodes, and in the bone marrow. During intestinal inflammation, proinflammatory cytokines such as TNFα, IL-1β, and LPS promote the expression of MAdCAM-1 and VCAM-1. Under normal conditions, α4β7 integrin is in a closed state on T lymphocytes. When T cells pass through the capillaries of the high endothelial venules in the gut-associated lymphoid tissue, L-selectin on the cell surface interacts with cell adhesion molecules, causing them to bind and roll along the endothelial surface. As the flow of T cells slows, the T cell's chemokine receptors are able to fully contact chemokines on the endothelial cells. Chemokines trigger the activation of α4β7 integrin, leading to a firm binding of α4β7 integrin to cell adhesion molecules to regulate lymphocyte migration. These cells may eventually migrate to the intestinal tissue, completing homing.

[0004] Inflammatory bowel disease (IBD) is a chronic, nonspecific intestinal inflammatory disease with an unknown etiology, including ulcerative colitis (UC) and Crohn's disease (CD). IBD is incurable, lifelong, recurrent, and disabling, and patients require long-term medication and regular follow-up visits. The pathogenesis of IBD is complex, and it is generally believed that it is caused by dysregulation of the mucosal immune response due to dysbiosis of the intestinal epithelial environment, genes, and microbial communities. Its main feature is the infiltration of a large number of inflammatory T cells into the intestinal lamina propria through cell adhesion and transport through the vascular wall, leading to excessive accumulation of intestinal mucosal lymphocytes. Studies have shown that α4β7 inhibitors inhibit T cell homing to the intestine during inflammation and can effectively reduce the accumulation of T cells in the intestine, thereby achieving the effect of treating IBD.

[0005] Currently available drugs targeting α4β7 have drawbacks such as the risk of serious adverse reactions due to their lack of selectivity and high production costs, which are a significant burden for patients who may need lifelong medication. Therefore, the development of selective α4β7 small molecule inhibitors is of great significance for the treatment of inflammatory bowel disease. Summary of the Invention

[0006] After intensive research, the inventors designed and synthesized a series of 3,4-dihydro-2H-benzo[b][1,4]dioxepane compounds, and screened their α4β7 integrin inhibitory activity. The research results showed that this type of compound has a potent and selective inhibitory effect on α4β7 integrin. The compound and the pharmaceutical composition containing the compound can be used to treat and / or prevent diseases related to α4β7 integrin activity, such as inflammatory bowel disease.

[0007] Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its tautomer, mesomorph, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal,

[0008] in:

[0009] Ring A is selected from C6-C 10 Aryl, 6-membered heterocyclic group, 6-membered monocyclic heteroaryl and 9-10-membered cyclic heteroaryl;

[0010] X1, X2, X3 and X4 are each independently CH or N;

[0011] Each R1 is independently selected from cyano, hydroxy, -NR a R b , halogen, -C(O)-R c 、-C(O)-OR c, carbamoyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-membered or 6-membered monocyclic heteroaryl, 9-10-membered cyclic heteroaryl, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6-membered heterocyclic group;

[0012] Each R2 is independently selected from cyano, hydroxy, -NR a R b , halogen, =O, -C(O)-R c 、-C(O)-OR c , carbamoyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-membered or 6-membered monocyclic heteroaryl, 9-10-membered cyclic heteroaryl, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6-membered heterocyclic group; or

[0013] Two R2 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl group;

[0014] Each R6 is independently selected from cyano, hydroxy, -NR a R b , halogen, =O, -C(O)-R c 、-C(O)-OR c , carbamoyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-membered or 6-membered monocyclic heteroaryl, 9-10-membered cyclic heteroaryl, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6-membered heterocyclic group;

[0015] Each R3 is independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, -NR a R b and -(C1-C6)alkylene-NR a R b , wherein at least one R3 is -(C1-C6)alkylene-NR a R b, the (C1-C6)alkylene group is optionally substituted by one or more substituents selected from the group consisting of C3-C6 cycloalkyl, C1-C6 alkyl, halogen, amino, cyano, nitro, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;

[0016] R4 is selected from C1-C6 alkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, -C3-C6 cycloalkylene-C1-C6 alkyl and C1-C6 haloalkyl;

[0017] R5 is hydrogen or C1-C6 alkyl;

[0018] R a and R b are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; or,

[0019] R a and R b Together with the nitrogen to which it is attached, it forms a 4-6 membered nitrogen-containing heterocyclic group, wherein the 4-6 membered nitrogen-containing heterocyclic group is optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen, amino, cyano, nitro, hydroxy, =O, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;

[0020] Each R c Each is independently hydrogen or C1-C6 alkyl;

[0021] m1 is 0, 1, or 2;

[0022] m2 is 0, 1, 2, 3, or 4;

[0023] m3 is 1, 2, 3 or 4; and

[0024] m4 is 2, 3, 4 or 5.

[0025] In a preferred embodiment, the compound represented by general formula (I), its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein ring A is selected from phenyl, naphthyl, pyridyl, dihydropyridyl, tetrahydropyridyl, pyranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl, preferably phenyl.

[0026] In a preferred embodiment, the compound represented by general formula (I), its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, is a compound represented by general formula (IIa), general formula (IIb), general formula (IIc) or general formula (IId) or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal,

[0027] wherein R1, R2, R3, R4, R5, R6, X1, X2, X3, X4, m1, m2, m3 and m4 are as defined in formula (I).

[0028] In a preferred embodiment, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein,

[0029] Selected from

[0030] In a preferred embodiment, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein:

[0031] Each R1 is independently selected from cyano, hydroxy, -NH2, halogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl, preferably halogen, C1-C6 haloalkyl and C1-C6 alkyl, more preferably fluorine, methyl and trifluoromethyl;

[0032] and / or

[0033] m1 is 0 or 1.

[0034] In a preferred embodiment, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein,

[0035] Each R2 is independently selected from cyano, hydroxy, -NH2, halogen, =O, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl, preferably =O and C1-C6 alkyl, more preferably =O, methyl and ethyl; or

[0036] Two R2 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl group, preferably a cyclopropyl group;

[0037] and / or

[0038] m2 is 0, 1, 2 or 3.

[0039] In a preferred embodiment, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein:

[0040] Each R3 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxy, halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, -NR a R b and -(C1-C6)alkylene-NR a R b , wherein at least one R3 is -(C1-C6)alkylene-NR a R b , the (C1-C6) alkylene group is optionally substituted by one or more C3-C6 cycloalkyl groups;

[0041] R a and R b are each independently hydrogen or C1-C6 alkyl; or,

[0042] R a and R b Together with the nitrogen to which it is attached, it forms a 4-6 membered nitrogen-containing heterocyclic group, wherein the 4-6 membered nitrogen-containing heterocyclic group is optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl;

[0043] Preferably, each R3 is independently selected from trifluoromethyl, methoxy, hydroxy, -(CH2)2-N(CH3)2, -CH2-N(CH3)2, -(CH2)3-N(CH3)2, cyclopropyl, -(CH2)2-azetidinyl, -(CH2)2-N(CH2CH3)2, -(CH2)3-N(CH3)2, -(CH2)2-morpholinyl, Methyl, -N(CH3)2, -(CH2)3-morpholinyl, and difluoromethyl;

[0044] and / or

[0045] m3 is 1 or 2.

[0046] In a preferred embodiment, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein R4 is C1-C6 alkyl or -C1-C6 alkylene-C3-C6 cycloalkyl, preferably isobutyl, propyl or -CH2-cyclopropyl.

[0047] In a preferred embodiment, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein R5 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, preferably R5 is hydrogen.

[0048] In a preferred embodiment, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein,

[0049] Each R6 is independently selected from cyano, hydroxy, -NH2, halogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl, preferably cyano, halogen, =O, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyl and C3-C6 cycloalkyl, more preferably cyclopropyl, methyl, chlorine, fluorine, cyano, cyclobutyl, methoxy, ethyl and trifluoromethyl;

[0050] and / or

[0051] m4 is 2, 3 or 4.

[0052] Typical compounds of the present invention include, but are not limited to:

[0053] Furthermore, typical compounds of the present invention include but are not limited to:

[0054] Its tautomers, meso racemates, racemates, enantiomers, diastereomers, deuterated forms, solvates, or mixtures thereof, or its pharmaceutically acceptable salts or co-crystals.

[0055] Another aspect of the present invention provides a method for preparing the compound represented by general formula (I) according to the present invention, which comprises the following steps:

[0056] The compound represented by the general formula III-1 and the compound represented by the general formula III-2 undergo a substitution reaction in an organic solvent under alkaline and heating conditions to obtain a compound represented by the general formula III-3.

[0057] Wherein, X is a leaving group, preferably a bromine atom, X1, X2, X3, X4, R3, R4 and m3 are as defined in the general formula (I),

[0058] The organic solvent is a physical mixture of one or more solvents, including methanol, ethanol, dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably N,N-dimethylformamide; the alkaline reagent providing alkaline conditions includes organic bases and inorganic bases, preferably potassium carbonate; the heating condition is 40°C-100°C, preferably 60°C;

[0059] The compound represented by the general formula III-3 undergoes hydrolysis reaction under alkaline conditions to obtain a compound represented by the general formula III.

[0060] wherein X1, X2, X3, X4, m3, R3 and R4 are as defined in the general formula (I),

[0061] The alkaline reagent providing alkaline conditions includes organic bases and inorganic bases, preferably lithium hydroxide;

[0062] The compound represented by the general formula IV-1 and tert-butylsulfenamide undergo condensation reaction in an organic solvent to obtain a compound represented by the general formula IV-2.

[0063] wherein Ring A, R1, R2, R6, m1, m2 and m4 are as defined in the general formula (I),

[0064] The organic solvent is a physical mixture of one or more solvents, including methanol, ethanol, dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably tetrahydrofuran;

[0065] The compound represented by the general formula IV-2 and the organometallic reagent undergo an addition reaction in an organic solvent to obtain a compound represented by the general formula IV-3.

[0066] Wherein, M is a metal atom, preferably a zinc atom, and ring A, R1, R2, R5, R6, m1, m2 and m4 are as defined in the general formula (I).

[0067] The organic solvent is a physical mixture of one or more solvents, including dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably tetrahydrofuran,

[0068] The compound represented by the general formula IV-3 is reacted in a solvent under acidic conditions to obtain a compound represented by the general formula IV.

[0069] wherein Ring A, R1, R2, R5, R6, m1, m2 and m4 are as defined in Formula (I),

[0070] The organic solvent is a physical mixture of one or more solvents, including water, methanol, ethanol, dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably 1,4-dioxane, and the acidic reagent providing acidic conditions includes organic acids and inorganic acids, organic acids include acetic acid, trifluoroacetic acid, etc., and inorganic acids include hydrochloric acid, sulfuric acid, hydrobromic acid, etc., preferably hydrochloric acid;

[0071] The compound represented by the general formula III and the compound represented by the general formula IV undergo condensation reaction in an organic solvent under alkaline conditions, optionally in the presence of a condensing agent, to obtain a compound represented by the general formula I.

[0072] wherein Ring A, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, m1, m2, m3 and m4 are as defined in Formula (I),

[0073] The organic solvent is a physical mixture of one or more solvents, including dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably acetonitrile; the alkaline reagent providing alkaline conditions includes organic bases and inorganic bases, organic bases include triethylamine, diisopropylethylamine, N-methylimidazole, imidazole, etc., inorganic bases include potassium carbonate, sodium carbonate, etc., preferably N-methylimidazole; the condensing agent includes tetramethyl chlorouronium hexafluorophosphate, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, etc., preferably tetramethyl chlorouronium hexafluorophosphate.

[0074] Another aspect of the present invention provides a pharmaceutical composition comprising the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0075] The present invention further provides use of the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of an α4β7 integrin inhibitor.

[0076] The present invention further provides use of the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of a medicament for preventing and / or treating diseases related to α4β7 integrin.

[0077] The present invention further provides the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same, for use as a medicament.

[0078] The present invention further provides the compound according to the present invention or its tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same, which is used as an α4β7 integrin inhibitor.

[0079] The present invention further provides the compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, for use in preventing and / or treating diseases related to α4β7 integrin activity.

[0080] The present invention further provides a method for inhibiting the activity of α4β7 integrin, which comprises administering to a subject in need thereof an effective amount of a compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0081] The present invention further provides a method for preventing and / or treating diseases related to α4β7 integrin activity, comprising administering to a subject in need thereof a preventively or therapeutically effective amount of a compound according to the present invention or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0082] In a preferred embodiment of the present invention, the disease associated with α4β7 integrin activity according to the present invention may be inflammatory bowel disease.

[0083] In a preferred embodiment of the present invention, the disease associated with α4β7 integrin activity according to the present invention may be inflammatory bowel disease, Crohn's disease, and the like.

[0084] The compounds of the present invention can form pharmaceutically acceptable acid addition salts with acids according to conventional methods in the field of the present invention. The acids include inorganic acids and organic acids, with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like being particularly preferred.

[0085] The compounds of the present invention can form pharmaceutically acceptable basic addition salts with bases according to conventional methods in the field of the present invention. The bases include inorganic bases and organic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide, and the like.

[0086] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions and may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. These tablets may be uncoated or may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period of time. For example, water-soluble taste masking substances such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending substances such as ethylcellulose, cellulose acetate butyrate may be used.

[0087] Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

[0088] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersants or wetting agents, which may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.

[0089] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oil suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0090] Dispersible powders and granules suitable for preparing aqueous suspensions can be provided with the active ingredient and a dispersant or wetting agent, a suspending agent, or one or more preservatives for mixing by the addition of water. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavorings, and coloring agents may also be added. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0091] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavorings, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain demulcents, preservatives, colorants, and antioxidants.

[0092] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. For example, the active ingredient may be dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.

[0093] The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in a nontoxic, parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. Furthermore, sterile fixed oils may conveniently be used as solvents or suspending media. For this purpose, any blended fixed oil, including synthetic mono- or diglycerides, may be used. Furthermore, fatty acids, such as oleic acid, may also be used to prepare injectable formulations.

[0094] The compounds of this invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thereby dissolves and releases the drug in the rectum. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycol.

[0095] It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the time of administration, the route of administration, the rate of excretion, the combination of drugs, etc. In addition, the optimal treatment regimen, such as the mode of treatment, the daily dosage of the general compound or the type of pharmaceutically acceptable salt, can be verified according to traditional treatment protocols.

[0096] The present invention may contain a compound represented by general formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to form a composition, and prepared into a clinically acceptable dosage form. The derivatives of the present invention may be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions. The compounds of the present invention may be used as the sole active ingredient or in combination with other drugs for treating diseases related to α4β7 integrin activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately or sequentially.

[0097] Definition of terms

[0098] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0099] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0100] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, an alkyl group containing 1 to 4 carbon atoms or an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment and may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0101] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12alkylene), more preferably an alkylene containing 1 to 6 carbon atoms (i.e., C 1-6 Alkylene), further preferably an alkylene containing 1 to 4 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (—CH—), 1,1-ethylene (—CH(CH)—), 1,2-ethylene (—CHCH)—, 1,1-propylene (—CH(CHCH)—), 1,2-propylene (—CHCH(CH)—), 1,3-propylene (—CHCHCHCH—), and 1,4-butylene (—CHCHCHCHCH—). Alkylene may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0102] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group containing 2 to 6 carbon atoms, more preferably an alkenyl group containing 2 to 4 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0103] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group having 2 to 6 carbon atoms, more preferably an alkynyl group having 2 to 4 carbon atoms, or more preferably an alkynyl group having 3 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, etc. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0104] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0105] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiro atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into a single spiroalkyl group, a double spiroalkyl group or a multi-spiroalkyl group, preferably a single spiroalkyl group and a double spiroalkyl group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl group. Non-limiting examples of spiroalkyl groups include:

[0106] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0107] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0108] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, tetrahydrobenzofuranyl, tetrahydrobenzoxazolyl, tetrahydrobenzisoxazolyl, cyclopentathienyl, tetrahydrobenzothiazolyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0109] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 4 to 12 ring atoms, of which 1 to 4 are heteroatoms; further preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably, it contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms; even more preferably, it contains 4 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups.

[0110] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 12 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0111] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 12 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0112] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 12 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0113] The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclyl ring.

[0114] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0115] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0116] The aryl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0117] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5 or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0118] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0119] The term "heteroalkyl" refers to a straight or branched chain alkyl group containing 1 to 20 carbon atoms and 1 to 3 heteroatoms selected from O, N, Si and S, wherein alkyl is as defined above, and wherein N and S may be optionally oxidized and N may be optionally quaternized.

[0120] The term "alkoxy" refers to -O-(alkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents can be one or more following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0121] The term "cycloalkoxy" refers to an -O-(cycloalkyl) group, wherein cycloalkyl is as defined above.

[0122] The term "heterocycloalkoxy" refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.

[0123] The term "cycloalkylthio" refers to -S-(cycloalkyl) where cycloalkyl is as defined above.

[0124] The term "heterocycloalkylthio" refers to an -S-(heterocyclyl) group wherein heterocyclyl is as defined above.

[0125] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0126] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0127] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0128] The term "hydroxy" refers to an -OH group.

[0129] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0130] The term "amino" refers to -NH2.

[0131] The term "cyano" refers to -CN.

[0132] The term "nitro" refers to -NO2.

[0133] The term "oxo" refers to =0.

[0134] The term "carboxy" refers to -C(O)OH.

[0135] The term "mercapto" refers to -SH.

[0136] The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0137] The term "acyl" refers to a compound containing a -C(O)R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0138] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0139] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0140] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert its biological activity.

[0141] Or "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

[0142] "Carrier" refers to a vehicle or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0143] Synthesis method of the compound of the present invention

[0144] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0145] In some embodiments, the compound represented by general formula (I) of the present invention can be prepared by Scheme 1.

[0146] Solution 1

[0147] wherein ring A, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, m1, m2, m3 and m4 are as defined in general formula (I); X is a leaving group, preferably a bromine atom; and M is a metal atom, preferably a zinc atom.

[0148] Step 1: The compound represented by the general formula III-1 and the compound represented by the general formula III-2 undergo a substitution reaction in an organic solvent under alkaline and heating conditions to obtain a compound represented by the general formula III-3.

[0149] The organic solvent is a physical mixture of one or more solvents, including methanol, ethanol, dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably N,N-dimethylformamide; the alkaline reagent providing alkaline conditions includes organic bases and inorganic bases, preferably potassium carbonate; the heating conditions are 40°C-100°C, preferably 60°C.

[0150] Step 2: The compound represented by the general formula III-3 undergoes hydrolysis reaction under alkaline conditions to obtain a compound represented by the general formula III.

[0151] The alkaline reagent providing alkaline conditions includes organic bases and inorganic bases, preferably lithium hydroxide;

[0152] Step 3: The compound represented by the general formula IV-1 and tert-butylsulfenamide undergo condensation reaction in an organic solvent, optionally in the presence of a catalyst, to obtain a compound represented by the general formula IV-2.

[0153] The organic solvent is a physical mixture of one or more solvents, including methanol, ethanol, dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably tetrahydrofuran; the catalyst includes tetraethyl titanate, copper sulfate, etc., preferably tetraethyl titanate.

[0154] Step 4: The compound represented by the general formula IV-2 and an organometallic reagent undergo an addition reaction in an organic solvent, optionally in the presence of a catalyst, to obtain a compound represented by the general formula IV-3.

[0155] The organic solvent is a physical mixture of one or more solvents, including dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably tetrahydrofuran.

[0156] Step 5: The compound represented by the general formula IV-3 is reacted in a solvent under acidic conditions to obtain a compound represented by the general formula IV.

[0157] The organic solvent is a physical mixture of one or more solvents, including water, methanol, ethanol, dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably 1,4-dioxane; the acidic reagents through acidic conditions include organic acids and inorganic acids, organic acids include acetic acid, trifluoroacetic acid, etc., inorganic acids include hydrochloric acid, sulfuric acid, hydrobromic acid, etc., preferably hydrochloric acid.

[0158] Step 6: The compound represented by the general formula III and the compound represented by the general formula IV undergo condensation reaction in an organic solvent under alkaline conditions, optionally in the presence of a condensing agent, to obtain a compound represented by the general formula I.

[0159] The organic solvent is a physical mixture of one or more solvents, including dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably acetonitrile; the alkaline reagent providing alkaline conditions includes organic bases and inorganic bases, organic bases include triethylamine, diisopropylethylamine, N-methylimidazole, imidazole, etc., inorganic bases include potassium carbonate, sodium carbonate, etc., preferably N-methylimidazole; the condensing agent includes tetramethyl chlorouronium hexafluorophosphate, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, etc., preferably tetramethyl chlorouronium hexafluorophosphate.

[0160] In some embodiments, the compound represented by general formula (IIa) of the present invention can be prepared by Scheme 2.

[0161] Option 2

[0162] wherein X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, m2, m1, m3 and m4 are as defined in formula (IIa); is a single bond or a double bond; X is a leaving group, preferably a bromine atom; M is a metal atom, preferably a zinc atom.

[0163] Step 1: A compound represented by the general formula IIa-1 and tert-butylsulfenamide undergo condensation reaction in an organic solvent, optionally in the presence of a catalyst, to obtain a compound represented by the general formula IIa-2.

[0164] The organic solvent is a physical mixture of one or more solvents, including methanol, ethanol, dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably tetrahydrofuran; the catalyst includes tetraethyl titanate, copper sulfate, etc., preferably tetraethyl titanate.

[0165] Step 2: The compound represented by the general formula IIa-2 and an organometallic reagent undergo an addition reaction in an organic solvent to obtain a compound represented by the general formula IIa-3.

[0166] The organic solvent is a physical mixture of one or more solvents, including dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably tetrahydrofuran.

[0167] Step 3: The compound represented by the general formula IIa-3 and the compound represented by the general formula IIa-4 are heated in a solvent in the presence of an optional catalyst and an alkaline reagent to cause a coupling reaction to obtain a compound represented by the general formula IIa-5.

[0168] The solvent is a physical mixture of one or more solvents, including organic solvents and inorganic solvents. The organic solvents include dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably a mixed solvent of 1,4-dioxane and water; the catalyst includes tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, palladium acetate, etc., preferably tris(dibenzylideneacetone)dipalladium, preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; the alkaline reagent includes organic bases and inorganic bases. Organic bases include triethylamine, diisopropylethylamine, N-methylimidazole, imidazole, etc., and inorganic bases include potassium carbonate, cesium carbonate, etc., preferably potassium carbonate; the heating conditions are 60°C-120°C, preferably 110°C.

[0169] Step 4: In a solvent containing the compound represented by the general formula IIa-5, under acidic conditions, a compound represented by the general formula IIa-6 is obtained.

[0170] The organic solvent is a physical mixture of one or more solvents, including water, methanol, ethanol, dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably 1,4-dioxane; the acidic reagent providing acidic conditions includes organic acids and inorganic acids, organic acids include acetic acid, trifluoroacetic acid, etc., inorganic acids include hydrochloric acid, sulfuric acid, hydrobromic acid, etc., preferably hydrochloric acid.

[0171] Step 5: The compound represented by the general formula III and the compound represented by the general formula IIa-6 undergo condensation reaction in an organic solvent under alkaline conditions, optionally in the presence of a condensing agent, to obtain a compound represented by the general formula IIa.

[0172] The organic solvent is a physical mixture of one or more solvents, including dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably acetonitrile; the alkaline reagent providing alkaline conditions includes organic bases and inorganic bases, organic bases include triethylamine, diisopropylethylamine, N-methylimidazole, imidazole, etc., inorganic bases include potassium carbonate, sodium carbonate, etc., preferably N-methylimidazole; the condensing agent includes tetramethyl chlorouronium hexafluorophosphate, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, etc., preferably tetramethyl chlorouronium hexafluorophosphate.

[0173] In some embodiments, the compound represented by general formula (IIb) of the present invention can be prepared by Scheme 3.

[0174] Option 3

[0175] wherein X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, m2, m1, m3 and m4 are as defined in formula (IIb); is a single bond or a double bond; X is a leaving group, preferably a bromine atom; M is a metal atom, preferably a zinc atom.

[0176] Step 1: A compound represented by the general formula IIb-1 and tert-butylsulfenamide undergo condensation reaction in an organic solvent, optionally in the presence of a catalyst, to obtain a compound represented by the general formula IIb-2.

[0177] The organic solvent is a physical mixture of one or more solvents, including methanol, ethanol, dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably tetrahydrofuran; the catalyst includes tetraethyl titanate, copper sulfate, etc., preferably tetraethyl titanate.

[0178] Step 2: The compound represented by the general formula IIb-2 and an organometallic reagent undergo an addition reaction in an organic solvent to obtain a compound represented by the general formula IIb-3.

[0179] The organic solvent is a physical mixture of one or more solvents, including dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably tetrahydrofuran.

[0180] Step 3: The compound represented by the general formula IIb-3 and the compound represented by the general formula IIb-4 are heated in a solvent in the presence of an optional catalyst and an alkaline reagent to cause a coupling reaction to obtain a compound represented by the general formula IIb-5.

[0181] The solvent is a physical mixture of one or more solvents, including organic solvents and inorganic solvents. The organic solvents include dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably a mixed solvent of 1,4-dioxane and water; the catalyst includes tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, palladium acetate, etc., preferably tris(dibenzylideneacetone)dipalladium, preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; the alkaline reagent includes organic bases and inorganic bases. Organic bases include triethylamine, diisopropylethylamine, N-methylimidazole, imidazole, etc., and inorganic bases include potassium carbonate, cesium carbonate, etc., preferably potassium carbonate; the heating conditions are 60°C-120°C, preferably 110°C.

[0182] Step 4: In a solvent containing the compound represented by the general formula IIb-5, under acidic conditions, a compound represented by the general formula IIb-6 is obtained.

[0183] The organic solvent is a physical mixture of one or more solvents, including water, methanol, ethanol, dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably 1,4-dioxane; the acidic reagent providing acidic conditions includes organic acids and inorganic acids, organic acids include acetic acid, trifluoroacetic acid, etc., inorganic acids include hydrochloric acid, sulfuric acid, hydrobromic acid, etc., preferably hydrochloric acid.

[0184] Step 5: The compound represented by the general formula III and the compound represented by the general formula IIb-6 undergo condensation reaction in an organic solvent under alkaline conditions, optionally in the presence of a condensing agent, to obtain a compound represented by the general formula IIb.

[0185] The organic solvent is a physical mixture of one or more solvents, including dichloromethane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc., preferably acetonitrile; the alkaline reagent providing alkaline conditions includes organic bases and inorganic bases, organic bases include triethylamine, diisopropylethylamine, N-methylimidazole, imidazole, etc., inorganic bases include potassium carbonate, sodium carbonate, etc., preferably N-methylimidazole; the condensing agent includes tetramethyl chlorouronium hexafluorophosphate, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, etc., preferably tetramethyl chlorouronium hexafluorophosphate. BRIEF DESCRIPTION OF THE DRAWINGS

[0186] Figure 1: Number of CFSE-stained T cells in Peyer's patches of mice after a single oral administration of 30 mpk of compound (n=5). DETAILED DESCRIPTION

[0187] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0188] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker dps300 nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0189] LC-MS measurements were performed using an 1100 Series LC / MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).

[0190] GC-MS was performed using a GCMS-QP2010 SE.

[0191] Preparative liquid chromatography was performed using an LC3000 high performance liquid chromatograph and an LC6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng). The chromatographic column was a Daisogel C18 10 μm 60A (20 mm × 250 mm).

[0192] High performance liquid chromatography (HPLC) was performed using a Shimadzu LC-20AD high pressure liquid chromatograph (Agilent TC-C18 250×4.6 mm 5 μm column) and a Shimadzu LC-2010AHT high pressure liquid chromatograph (Phenomenex C18 250×4.6 mm 5 μm column).

[0193] The thin layer chromatography silica gel plate used was Qingdao Ocean Chemical GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15 mm to 0.2 mm, and the specification used for thin layer chromatography separation and purification products was 0.4 mm to 0.5 mm.

[0194] Column chromatography generally uses Qingdao marine silica gel 100-200 mesh and 200-300 mesh silica gel as the carrier.

[0195] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Yinuokai, Nanjing Yaoshi, Anaiji Chemical and other companies.

[0196] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0197] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0198] A CEM Discover SP microwave reactor was used for the microwave reaction.

[0199] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0200] Unless otherwise specified in the examples, the reaction temperature is room temperature, particularly 20°C to 30°C.

[0201] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0202] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound include: A: dichloromethane and methanol system, B: petroleum ether, ethyl acetate and dichloromethane system, C: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0203] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention.

[0204] Example 1: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (1a and 1b)

[0205] Step 1: Preparation of 5-bromo-2,3-dihydroxybenzaldehyde (1-1).

[0206] 5-Bromo-2-hydroxy-3-methoxybenzaldehyde (6.00 g, 26.97 mmol) was dissolved in anhydrous dichloromethane (200.0 mL) at 0°C under a nitrogen atmosphere. A 1 M solution of boron tribromide in dichloromethane (65.0 mL, 65.00 mmol) was slowly added to the mixture. The mixture was reacted at 0°C for 1 hour. The reaction system was allowed to warm naturally and stirred for 2.5 hours. The mixture was then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 5%-50%) to give 5.53 g of the title compound as a colorless oil in a yield of 98.1%.

[0207] LC-MS: m / z 217.0, 219.0 [M+H] + .

[0208] Step 2: Preparation of 8-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde (1-2).

[0209] At room temperature under a nitrogen atmosphere, 5-bromo-2,3-dihydroxybenzaldehyde (5.53 g, 25.48 mmol), 1,3-dibromopropane (16.80 g, 83.16 mmol), and diisopropylethylamine (10.70 g, 83.94 mmol) were dissolved in N,N-dimethylformamide (50.0 mL) and reacted at 80°C for 16 hours. The reaction was quenched with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The filtrate was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to obtain 6.25 g of the title compound as a colorless oil in a 95.4% yield.

[0210] LC-MS: m / z 257.0, 259.0 [M+H] + .

[0211] Step 3: Preparation of (R,Z)-N-((8-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)methylene)-2-methylpropane-2-sulfonamide (1-3).

[0212] Under a nitrogen atmosphere at below 30°C, 8-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde (6.25 g, 24.32 mmol) and (R)-2-methylpropane-2-sulfonamide (3.54 g, 29.26 mmol) were dissolved in anhydrous tetrahydrofuran (50.0 mL). Tetraethyl titanate (7.65 mL, 36.50 mmol) was slowly added, and the mixture was allowed to react at 40°C for 1 hour. The reaction was quenched with a mixture of 150 mL of water and 150 mL of ethyl acetate, filtered, and the filter cake washed with ethyl acetate (300 mL). The combined organic phases were washed with saturated brine (200 mL) and concentrated under reduced pressure to afford 4.67 g of the title compound as a yellow oil in a 53.3% yield.

[0213] LC-MS: m / z 360.1, 362.1 [M+H] + .

[0214] Step 4: Preparation of (S)-methyl 3-(8-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (1-4).

[0215] At room temperature and under nitrogen atmosphere, zinc powder (10.14 g, 156 mmol) and anhydrous tetrahydrofuran (50.0 mL) were added to a reaction flask, and trimethylsilyl chloride (1.31 mL, 10.31 mmol) was slowly added. After reacting at 50°C for 1 hour, the reaction system was cooled to room temperature, and methyl 2-bromoacetate (7.36 mL, 77.74 mmol) was added dropwise. The reaction system was transferred to 50°C and continued to react for 1 hour. After cooling to room temperature, (R,Z)-N-((8-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)methylene)-2-methylpropane-2-sulfonamide (4.67 g, 12.97 mmol) was dissolved in anhydrous tetrahydrofuran (7.0 mL) and added dropwise to the reaction system. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with a mixture of 150 mL of water and 150 mL of ethyl acetate, filtered, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-50%) to give 4.74 g of the title compound as a yellow oil in a yield of 84.2%.

[0216] LC-MS: m / z 434.1,436.1[M+H] + .

[0217] Step 5: Preparation of (S)-methyl 3-(((R)-tert-butylsulfinyl)amino)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoate (1-5).

[0218] At room temperature under nitrogen atmosphere, methyl (S)-3-(8-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-(((R)-tert-butylsulfinyl)amino)propanoate (4.74 g, 10.92 mmol), 2,6-dimethylphenylboronic acid (3.28 g, 22.01 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (798 mg, 1.09 mmol), and potassium carbonate (3.01 g, 21.65 mmol) were dissolved in a mixed solvent of dioxane (50.0 mL) and water (10.0 mL). The reaction system was moved to 110°C for 2 hours. The reaction was quenched by adding water (150 mL), extracted with ethyl acetate (200 mL x 3), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-50%) to give 530 mg of the title compound as a colorless oil in a yield of 10.5%.

[0219] LC-MS: m / z 460.1[M+H] + .

[0220] Step 6: Preparation of (S)-methyl 3-amino-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoate (1-6).

[0221] Methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoate (530 mg, 1.15 mmol) was dissolved in dioxane (3.0 mL) at room temperature. 4 M hydrochloric acid solution in dioxane (1.40 mL, 5.60 mmol) was added and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure and washed three times with methanol to obtain 409 mg of a crude yellow oily product, which was used directly in the next step.

[0222] LC-MS: m / z 356.2[M+H] + .

[0223] Step 7: Preparation of methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoate (1-7).

[0224] Methyl (S)-3-amino-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoate (409 mg, 1.49 mmol), 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)yl)-4-methylpentanoic acid (519 mg, 1.49 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (836 mg, 2.98 mmol) were dissolved in acetonitrile (7.0 mL) at room temperature. N-methylimidazole (475 uL, 5.96 mmol) was added and the mixture was reacted at room temperature for 2 hours. The reaction was quenched with water (50 mL), extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 420 mg of the title compound as a yellow solid, with a yield of 53.2%.

[0225] LC-MS: m / z 686.2[M+H] + .

[0226] Step 8: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (1a and 1b).

[0227] Methyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoate (420 mg, 0.61 mmol) was dissolved in a mixed solvent of methanol (6.0 mL) and water (2.0 mL) at room temperature. Lithium hydroxide monohydrate (128 mg, 3.06 mmol) was added and the mixture was reacted at room temperature for 1 hour. 1N hydrochloric acid solution was added dropwise to adjust the pH to 6-7, and the mixture was concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid phase separation (chromatographic column model: Daisogei 30mm*250mm, C18, 10μm 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid) to obtain a pair of diastereomers:

[0228] 1a, white solid, 58 mg, yield 14.2%.

[0229] LC-MS: m / z 672.2[M+H] + .

[0230] 1H-NMR (400MHz, CD3OD) δ7.87 (s, 1H), 7.10-6.99 (m, 3H), 6.74 (s, 1H), 6.64 (d, 1H, J= 2.0Hz),6.58(d,1H,J=2.0Hz),5.67-5.63(m,1H),5.60-5.56(m,1H),4.32-4.19(m,3 H),4.14-4.08(m,1H),3.13-3.01(m,2H),2.94-2.92(m,2H),2.81-2.61(m,8H),2.22 -2.14(m,2H),1.98-1.93(m,5H),1.82(s,3H),1.47-1.30(m,2H),0.96-0.90(m,6H).

[0231] 1b, white solid, 76 mg, yield 18.5%.

[0232] LC-MS: m / z 672.2[M+H] + .

[0233] 1 H-NMR(400MHz,CD3OD)δ7.82(s,1H),7.12-7.04(m,3H),6.89(s,1H),6.68(s,1H),6.64 (s,1H),5.68-5.66(m,1H),5.62-5.58(m,1H),4.35-4.23(m,3H),4.17-4.16(m,1H),3.2 7-3.20(m,2H),3.00(m,2H),2.82(s,6H),2.62-2.57(m,1H),2.51-2.45(m,1H),2.22-2 .21(m,2H),1.99-1.92(m,7H),1.76-1.69(m,1H),1.40-1.30(m,2H),0.87-0.86(m,6H).

[0234] Example 2: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (2a and 2b)

[0235] Step 1: Preparation of 3-bromo-4,5-dihydroxybenzaldehyde (2-1).

[0236] At 0°C under a nitrogen atmosphere, 3-bromo-4-hydroxy-5-methoxybenzaldehyde (2.50 g, 10.82 mmol) was dissolved in anhydrous dichloromethane (100 mL). A 1 M solution of boron tribromide in dichloromethane (27.0 mL, 27.00 mmol) was slowly added. The mixture was reacted at 0°C for 1 hour. The reaction system was allowed to warm naturally and stirred for 2.5 hours. The mixture was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 5%-50%) to give 2.02 g of the title compound as a colorless oil in a yield of 85.3%.

[0237] LC-MS: m / z 217.0, 219.0 [M+H] + .

[0238] Step 2: Preparation of 9-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepane-7-carbaldehyde (2-2).

[0239] 3-Bromo-4,5-dihydroxybenzaldehyde (2.00 g, 9.21 mmol), 1,3-dibromopropane (5.58 g, 27.62 mmol), and diisopropylethylamine (3.56 g, 27.60 mmol) were dissolved in N,N-dimethylformamide (30.0 mL) at room temperature under a nitrogen atmosphere and reacted at 80°C for 16 hours. The reaction was quenched with 250 mL of water and extracted with ethyl acetate (250 mL x 3). The filtrate was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to afford 2.26 g of the title compound as a colorless oil in a 95.4% yield.

[0240] LC-MS: m / z 257.0, 259.0 [M+H] + .

[0241] Prepared by the synthetic method of Reference Example 1:

[0242] 2a, white solid.

[0243] LC-MS: m / z 672.2[M+H] + .

[0244] 1H-NMR (400 MHz, CD3OD) δ 7.89 (s, 1H), 7.10 - 7.00 (m, 3H), 6.93 (d, J = 2.0 Hz, 1H), 6.81 (s, 1H), 6.60 (d, J = 2.0 Hz, 1H), 5.68 (t, J = 8.0 Hz, 1H), 5.23 (t, J = 8.0 Hz, 1H), 4.15 (t J = 5.2 Hz, 2H,), 3.96 (t, J = 5.2 Hz, 2H), 3.15 - 3.13 (m, 2H), 2.96 - 2.94 (m, 2H), 2.80 (s, 6H), 2.71 - 2.68 (m, 2H), 2.09 - 2.06 (m, 2H), 1.98 - 1.94 (m, 5H), 1.88 (s, 3H), 1.45 - 1.39 (m, 1H), 1.29 (m, 1H), 0.94 (t, J = 7.6 Hz, 6H).

[0245] 2b, white solid.

[0246] LC-MS: m / z 672.2 [M+H] + .

[0247] 1 H-NMR (400 MHz, CD3OD) δ 7.83 (s, 1H), 7.12 - 7.03 (m, 3H), 6.97 (s, 1H), 6.89 (s, 1H), 6.64 (s, 1H), 5.61 (t, J = 7.6 Hz, 1H), 5.34 - 5.33 (m, 1H), 4.19 (t, J = 5.2 Hz, 2H), 3.99 (t, J = 5.2 Hz, 2H), 3.27 - 3.22 (m, 2H), 2.98 (t, J = 7.2 Hz, 2H), 2.84 (s, 6H), 2.62 - 2.49 (m, 2H), 2.10 (t, J = 5.2 Hz, 2H), 1.98 - 1.92 (m, 7H), 1.74 - 1.67 (m, 1H), 1.40 - 1.29 (m, 2H), 0.90 - 0.88 (m, 6H).

[0248] Example 3: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (3a and 3b)

[0249] Referring to the synthesis method of Example 1, (4-fluoro-2,6-dimethylphenyl)boric acid was used instead of (2,6-dimethylphenyl)boric acid to prepare:

[0250] 3a, white solid.

[0251] LC-MS: m / z 690.2[M+H] + .

[0252] 3b, white solid.

[0253] LC-MS: m / z 690.2[M+H] + .

[0254] 1 H-NMR(400MHz,CD3OD)δ9.02(d,J=8.0Hz,1H),7.93(s,1H),6.90(s,1H),6 .84(d,J=9.6Hz,2H),6.72-6.69(m,2H),5.76-5.63(m,2H),4.38-4.16(m,4 H),3.37-3.35(m,2H),3.05-2.99(m,8H),2.85-2.75(m,2H),2.30-2.19(m, 2H),2.03(s,6H),1.77-1.93(m,2H),1.42-1.35(m,1H),0.92-0.88(m,6H).

[0255] Example 4: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-homomethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-homomethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (4a and 4b)

[0256] Referring to the synthesis method of Example 1, (trimethylphenyl)boric acid was used instead of (2,6-dimethylphenyl)boric acid to prepare:

[0257] 4a, white solid.

[0258] LC-MS: m / z 686.2[M+H] + .

[0259] 4b, white solid.

[0260] LC-MS: m / z 686.2[M+H] + .

[0261] 1 H-NMR(400MHz,CD3OD)δ9.02(d,J=8.0Hz,1H),7.94(s,1H),6.90(s,3H),6.72-6.67(m,2H),5.76-5.64(m,2H),4.38-4.15(m,4H),3 .37-3.35(m,2H),3.05-2.99(m,8H),2.85-2.74(m,2H),2.33-2.19(m,5H),2.04-1.77(m,8H),1.41-1.34(m,1H),0.90-0.87(m,6H).

[0262] Example 5: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (5a and 5b)

[0263] Step 1: Preparation of 6-fluoro-2,3-dimethoxybenzaldehyde (5-1).

[0264] Under a nitrogen atmosphere, 4-fluoro-1,2-dimethoxybenzene (10.00 g, 64.10 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL). A 2.5 M solution of n-butyllithium in n-hexane (30.7 mL, 76.75 mmol) was slowly added dropwise at -78°C. The mixture was allowed to react for 1 hour at -78°C. N,N-dimethylformamide (10.0 mL, 0.13 mol) was then added and allowed to react for 2 hours at -78°C. The reaction solution was quenched with saturated ammonium chloride solution (250 mL) and extracted with ethyl acetate (250 mL x 3). The organic phase was washed with saturated brine (250 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 40:1-10:1) to obtain 8.51 g of the title compound as a colorless oil in a 72.1% yield.

[0265] LC-MS: m / z 185.1[M+H] + .

[0266] Step 2: Preparation of 3-bromo-2-fluoro-5,6-dimethoxybenzaldehyde (5-2).

[0267] Under a nitrogen atmosphere at room temperature, 6-fluoro-2,3-dimethoxybenzaldehyde (8.51 g, 46.25 mmol) was dissolved in 200 ml of dichloromethane. Liquid bromine (8.13 g, 50.81 mmol) was slowly added dropwise at 0°C, and the reaction was continued at 0°C for 1 hour. The reaction was quenched with saturated sodium thiosulfate solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 40:1-10:1) to obtain 3.65 g of the compound as a white solid in a 31.4% yield.

[0268] LC-MS: m / z 263.1, 264.1 [M+H] + .

[0269] Step 3: Preparation of 3-bromo-2-fluoro-5,6-dihydroxybenzaldehyde (5-3).

[0270] Under a nitrogen atmosphere at room temperature, 3-bromo-2-fluoro-5,6-dimethoxybenzaldehyde (3.65 g, 13.88 mmol) was dissolved in 200 mL of dichloromethane. A 1 M solution of boron tribromide in dichloromethane (40.0 mL, 40.00 mmol) was added dropwise at 0°C. The mixture was allowed to react for 4 hours. The reaction was quenched by the addition of water (100 mL). The mixture was extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine (150 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain 1.28 g of the title compound in a 39.2% yield.

[0271] LC-MS: m / z 235.1, 237.1 [M+H] + .

[0272] Referring to the synthesis method of Example 1, 3-bromo-2-fluoro-5,6-dihydroxybenzaldehyde was used instead of 5-bromo-2,3-dihydroxybenzaldehyde to obtain:

[0273] 5a, white solid.

[0274] LC-MS: m / z 690.4 [M+H] + .

[0275] 1H NMR(400MHz,CD3OD)δ9.00(d,J=7.6Hz,1H),7.91(s,1H),7.17-7.06(m,3H),6.86(s, 1H),6.66(d,J=7.2Hz,1H),5.92-5.78(m,2H),4.35-4.33(m,1H),4.27-4.21(m,1H),4 .18-4.08(m,2H),3.37-3.34(m,1H),3.32-3.26(m,3H),3.15-2.95(m,8H),2.88-2.7 9(m,1H),2.18-2.27(m,2H),2.07-1.94(m,7H),1.50-1.40(m,1H),1.00-0.96(m,6H).

[0276] 5b, white solid.

[0277] LC-MS: m / z 690.4 [M+H] + .

[0278] 1 H-NMR(400MHz,CD3OD)δ9.11(d,J=7.6Hz,1H),7.94(s,1H),7.19-7.10(m,3H),6.92(s ,1H),6.71(d,J=7.6Hz,1H),5.92-5.86(m,1H),5.78(t,J=8.0Hz,1H),4.42-4.30(m,2 H),4.26-4.12(m,2H),3.40-3.35(m,2H),3.09-2.99(m,8H),2.89-2.83(m,1H),2.30- 2.20(m,3H),2.05(s,6H),1.84(t,J=7.6Hz,2H),1.41-1.36(m,1H),0.93-0.89(m,6H).

[0279] Example 6: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(7-fluoro-8-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(7-fluoro-8-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (6a and 6b)

[0280] Referring to the synthesis method of Example 5, (4-fluoro-2,6-dimethylphenyl)boric acid was used instead of (2,6-dimethylphenyl)boric acid to prepare:

[0281] 6a, white solid.

[0282] LC-MS: m / z 708.4 [M+H] + .

[0283] 1 H-NMR(400MHz,CD3OD)δ9.00(d,J=7.6Hz,1H),7.91(s,1H),6.90-6.83(m,3H),6 .66(d,J=7.6Hz,1H),5.88-5.76(m,2H),4.40-4.33(m,1H),4.27-4.21(m,1H),4 .19-4.08(m,2H),3.32-3.26(m,2H),3.16-2.93(m,9H),2.86-2.81(m,1H),2.24 -2.19(m,2H),2.10-1.93(m,8H),1.49-1.39(m,1H),0.98(dd,J=9.6,6.4Hz,6H).

[0284] 6b, white solid.

[0285] LC-MS: m / z 708.4 [M+H] + .

[0286] 1 H-NMR(400MHz,CD3OD)δ9.10(d,J=7.6Hz,1H),7.94(s,1H),6.92-6.86(m,3H),6 .71(d,J=7.2Hz,1H),5.90-5.84(m,1H),5.78(t,J=8.0Hz,1H),4.42-4.30(m,2H) ,4.26-4.12(m,2H),3.40-3.34(m,2H),3.06-2.83(m,10H),2.30-2.19(m,2H),2. 05(s,6H),1.84(t,J=7.6Hz,2H),1.39-1.34(m,1H),0.91(dd,J=12.0,6.8Hz,6H)

[0287] Example 7: Preparation of (S)-3-((R)-2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (7a and 7b)

[0288] Step 1: Preparation of (E)-methyl 2-(3-(2-ethoxyvinyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoate (7-1).

[0289] At room temperature and under nitrogen atmosphere, methyl 2-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoate (200 mg, 0.61 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (264 mg, 1.22 mmol), palladium acetate (13.7 mg, 61 μmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (58 mg, 0.12 mmol), potassium carbonate (169 mg, 1.22 mmol), dioxane (15.0 mL) and water (3.0 mL) were added to a reaction flask. The reaction system was moved to 110°C for 2 hours. The reaction was quenched by adding water (100 mL), extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-50%) to give 180 mg of the title compound as a colorless oil in a yield of 81.1%.

[0290] LC-MS: m / z 363.1[M+H] + .

[0291] Step 2: Preparation of methyl 4-methyl-2-(6-oxo-3-(2-oxoethyl)-4-(trifluoromethyl)pyridazin-1(6H)-yl)pentanoate (7-2).

[0292] Methyl (E)-2-(3-(2-ethoxyvinyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoate (180 mg, 0.50 mmol) was dissolved in dichloromethane (4.0 mL) at room temperature, and trifluoroacetic acid solution (1.0 mL) was added. The mixture was reacted at room temperature for 4 hours. Water (50 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phase was washed with saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 160 mg of a yellow oily crude product, which was used directly in the next step.

[0293] LC-MS: m / z 335.2[M+H] + .

[0294] Step 3: Preparation of methyl 2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoate (7-3).

[0295] Methyl 4-methyl-2-(6-oxo-3-(2-oxoethyl)-4-(trifluoromethyl)pyridazin-1(6H)-yl)pentanoate (160 mg, 0.44 mmol), dimethylamine hydrochloride (278 mg, 1.32 mmol), and 1,2-dichloroethane (10.0 mL) were added to a reaction flask at room temperature and stirred at room temperature for 0.5 hour. Sodium triacetoxyborohydride (203 mg, 0.96 mmol) was added and the mixture was reacted at room temperature for 1 hour. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The filtrate was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-50%) to give 120 mg of the title compound as a yellow oil, with a total yield of 76.3% over two steps.

[0296] LC-MS: m / z 364.1[M+H] + .

[0297] Step 4: Preparation of 2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoic acid (7-4).

[0298] Methyl 2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoate (120 mg, 0.33 mmol), lithium hydroxide monohydrate (69.1 mg, 1.64 mmol), methanol (9.0 mL), and water (3.0 mL) were added to a reaction flask at room temperature and allowed to react for 2 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 7-8, and the mixture was concentrated under reduced pressure to yield 100 mg of the crude title compound as a yellow solid, which was used directly in the next step.

[0299] LC-MS: m / z 350.3 [M+H] + .

[0300] Step 5: Preparation of methyl (3S)-3-(2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoate (7-5).

[0301] At room temperature, 2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoic acid (100 mg, 0.28 mmol), (S)-methyl 3-amino-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoate (152 mg, 0.43 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (158 mg, 0.57 mmol) and N-methylimidazole (91 uL, 1.14 mmol) were added to acetonitrile (10.0 mL) and reacted at room temperature for 2 hours. The reaction was quenched with water (50 mL), extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 200 mg of the crude product of the title compound as a yellow solid, which was used directly in the next reaction.

[0302] LC-MS: m / z 687.2[M+H] + .

[0303] Step 6: Preparation of (S)-3-((R)-2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (7a and 7b).

[0304] Methyl (3S)-3-(2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoate (200 mg, 0.29 mmol) was dissolved in a mixed solvent of methanol (6.0 mL) and water (2.0 mL) at room temperature. Lithium hydroxide monohydrate (61 mg, 1.45 mmol) was added and the mixture was reacted at room temperature for 1 hour. 1N hydrochloric acid solution was added dropwise to adjust the pH to 6-7, and the mixture was concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid) to obtain a pair of diastereomers:

[0305] 7a, white solid, 9.0 mg, yield 4.3%.

[0306] LC-MS: m / z 673.2[M+H] + .

[0307] 1 H-NMR (400MHz, CD3OD) δ7.36 (s, 1H), 7.14-7.05 (m, 3H), 6.68-6.63 (m, 2H), 5.69-5.65 (m, 1H), 5.55 (t, J = 6.0Hz, 1H), 4.30-4.14 (m, 4H), 3.56 -3.49(m,2H),3.27-3.13(m,3H),2.73(s,6H),2.63-2.60(m,1H),2.25 -2.11(m,4H),2.06-1.84(m,7H),1.47-1.45(m,1H),0.95-0.93(m,6H).

[0308] 7b, white solid, 3.0 mg, yield 1.5%.

[0309] LC-MS: m / z 673.2[M+H] + .

[0310] 1 H-NMR (400MHz, CD3OD) δ7.42(s,1H),7.15-7.07(m,3H),6.69(s,2H),5.72(t,J=7.6Hz,1H ),5.66-5.63(m,1H),5.36(t,J=4.4Hz,1H),4.32(t,J=5.6Hz,2H),4.27-4.19(m,2H),3.74 -3.68(m,1H),3.50-3.49(m,1H),3.28-3.26(m,1H),3.16-3.15(m,1H),2.96(s,6H),2.74 -2.68(m,1H),2.27-2.19(m,3H),2.06-1.83(m,8H),1.65-1.60(m,1H),0.92-0.88(m,6H).

[0311] Example 8: (S)-3-(8-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((R)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyrimidin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of )-3-(8-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyrimidin-1(2H)-yl)-4-methylpentanamido)propanoic acid (8a and 8b)

[0312] Step 1: Preparation of methyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyrimidin-1(2H)-yl)-4-methylpentanoate.

[0313] 5-Bromo-4-(trifluoromethyl)pyrimidin-2(1H)-one (3.10 g, 12.76 mmol), methyl 2-bromo-4-methylpentanoate (5.35 g, 25.60 mmol), and potassium carbonate (2.40 g, 17.27 mmol) were added to N,N-dimethylformamide (30.0 mL) at room temperature and reacted at 80°C for 2 hours. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The filtrate was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-80%) to obtain 532 mg of the title compound as a light yellow oil in an 11.2% yield.

[0314] LC-MS: m / z 370.8, 372.8 [M+H] + .

[0315] With reference to the synthetic method of Example 7, 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyrimidin-1(2H)-yl)-4-methylpentanoate was substituted for 2-(3-bromo-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoate, and 3-fluoroazetidine hydrochloride was substituted for dimethylamine hydrochloride to prepare:

[0316] 8a, white solid.

[0317] LC-MS: m / z 721.2[M+H] + .

[0318] 8b, white solid.

[0319] LC-MS: m / z 721.2[M+H] + .

[0320] 1H-NMR(400MHz,CD3OD)δ8.53(s 1H),6.83(d,J=9.6Hz,2H),6.60-6.57(m,2H),5.56(t,J=6.8Hz,1H),5.30(dd,J=9.4,4.0H z,1H),5.25-5.07(m,1H),4.34-4.29(m,1H),4.27-4.22(m,1H),4.19-4.13(m,1H),4.09-4. 04(m,1H),3.84-3.74(m,2H),3.45-3.42(m,1H),3.40-3.36(m,1H),2.88-2.76(m,6H),2.2 3-2.12(m,2H),1.99-1.84(m,8H),1.76-1.70(m,1H),1.36-1.31(m,1H),0.99-0.93(m,6H).

[0321] Example 9: Preparation of (S)-3-(8-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((R)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-3-methyl-2-oxopyrazin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S)-3-(8-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-3-methyl-2-oxopyrazin-1(2H)-yl)-4-methylpentanamido)propanoic acid (9a and 9b)

[0322] With reference to the synthetic method of Example 7, 2-(5-bromo-3-methyl-2-oxopyrazine-1(2H)-yl)-4-methylpentanoate was substituted for 2-(3-bromo-6-oxo-4-(trifluoromethyl)pyridazine-1(6H)-yl)-4-methylpentanoate, and 3-fluoroazetidine hydrochloride was substituted for dimethylamine hydrochloride to prepare:

[0323] 9a, white solid.

[0324] LC-MS: m / z 667.4 [M+H] + .

[0325] 1H-NMR (400MHz, CD3OD) δ7.28 (s, 1H), 6.88 (dd, J = 8.0Hz, 5.6Hz, 2H), 6.59 (d, J = 1.6Hz ,1H),6.50(d,J=1.6Hz,1H),5.44(t,J=4.8Hz,1H),5.37-5.26(m,2H),4.37-3.99(m,7 H),3.81-3.69(m,2H),3.24-3.09(m,2H),2.80-2.65(m,4H),2.52(s,3H),2.27-2.14 (m,2H),2.05(s,3H),2.00-1.77(m,6H),0.99(d,J=6.4Hz,3H),0.94(d,J=6.4Hz,3H).

[0326] 9b, white solid.

[0327] LC-MS: m / z 667.4 [M+H] + .

[0328] 1 H-NMR (400MHz, CD3OD) δ7.75 (s, 1H), 6.84-6.82 (m, 2H), 6.73 (d, J = 6.0Hz, 1H), 6.6 2(d,J=6.0Hz,1H),5.45-5.41(m,1H),5.28-5.11(m,2H),4.42-4.02(m,7H),3.62-3 .41(m,2H),3.15-2.89(m,2H),2.77-2.71(m,1H),2.53(s,3H),2.32-2.10(m,4H), 2.05-1.83(m,9H),1.68-1.62(m,1H),0.98(d,J=6.4Hz,3H),0.91(d,J=6.4Hz,3H).

[0329] Example 10: (S)-3-(7-fluoro-8-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((R)-2-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of 3-(7-fluoro-8-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((S)-2-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylpentanamido)propanoic acid (10a and 10b)

[0330] Referring to the synthesis method of Example 6, 2-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylpentanoic acid was used instead of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0331] 10a, white solid.

[0332] LC-MS: m / z 685.0 [M+H] + .

[0333] 1 H-NMR (400MHz, DMSO-d6) δ7.96(d,J=7.6Hz,1H),7.26(s,1H),6.97(d,J=9.6Hz,2H),6.68 (d,J=7.6Hz,1H),5.63-5.57(m,1H),5.42-5.38(m,1H),5.14-4.96(m,1H),4.16-3.98(m, 4H),3.53-3.46(m,4H),3.08-3.00(m,2H),2.77-2.59(m,4H),2.47-2.45(m,1H),2.11-2. 08(m,2H),2.04-1.95(m,9H),1.72-1.65(m,1H),1.30-1.23(m,1H),0.80(t,J=8.0Hz,6H).

[0334] 10b, white solid.

[0335] LC-MS: m / z 685.0 [M+H] + .

[0336] 1 H-NMR(400MHz,DMSO-d6)δ8.07(d,J=8.0Hz,1H),7.28(s,1H),6.97(d,J=10.0Hz ,2H),6.68(d,J=7.2Hz,1H),5.65-5.60(m,1H),5.43-5.39(m,1H),5.18-4.98(m ,1H),4.18-4.00(m,4H),3.59-3.50(m,4H),3.13-3.04(m,2H),2.75-2.53(m,6H ),2.13-1.94(m,10H),1.63-1.58(m,1H),1.29-1.25(m,1H),0.80-0.77(m,6H).

[0337] Example 11: (S)-3-(7-(4-fluoro-2,6-dimethylphenyl)-2H,4Hspiro[benzo[b][1,4]dioxepane-3,1'-cyclopropane]-9-yl)-3-((R)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of )-3-(7-(4-fluoro-2,6-dimethylphenyl)-2H,4Hspiro[benzo[b][1,4]dioxepane-3,1'-cyclopropane]-9-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (11a and 11b)

[0338] Step 1: Preparation of 8-bromo-2H,4H-spiro[benzo[b][1,4]dioxepane-3,1'-cyclopropane]-6-carbaldehyde (11-1).

[0339] 5-Bromo-2,3-dihydroxybenzaldehyde (5.30 g, 24.42 mmol), 1,1-bis(bromomethyl)cyclopropane (16.70 g, 73.24 mmol), and diisopropylethylamine (9.45 g, 73.26 mmol) were dissolved in N,N-dimethylformamide (50.0 mL) at room temperature under a nitrogen atmosphere and reacted at 80°C for 16 hours. The reaction was quenched with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The filtrate was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to obtain 6.25 g of the title compound as a colorless oil in a 90.4% yield.

[0340] LC-MS: m / z 283.0, 285.0 [M+H] + .

[0341] With reference to the synthetic method of Example 1, 8-bromo-2H,4H-spiro[benzo[b][1,4]dioxepane-3,1'-cyclopropane]-6-carbaldehyde was used instead of 8-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde, (4-fluoro-2,6-dimethylphenyl)boric acid was used instead of (2,6-dimethylphenyl)boric acid, and 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was used instead of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to prepare:

[0342] 11a, white solid.

[0343] LC-MS: m / z 746.7[M+H] + .

[0344] 11b, white solid.

[0345] LC-MS: m / z 746.7[M+H] + .

[0346] 1 H-NMR(400MHz,CD3OD)δ7.86(s,1H),6.91(s,1H),6.86(s,1H),6.84(s,1H),6.77(d,J=2.0Hz,1H), 6.72(d,J=2.0Hz,1H),5.75-5.66(m,2H),5.50-5.33(m,2H),4.56-4.47(m,2H),4.35-4.24(m,2H),4 .12-4.02(m,2H),3.96(m,2H),3.51-3.39(m,2H),2.91-2.88(m,2H),2.79-2.72(m,2H),2.21(t,J=7 .6Hz,1H),2.04(s,6H),1.94-1.77(m,2H),1.66-1.59(m,1H),0.94-0.89(m,6H),0.80-0.69(m,4H).

[0347] Example 12: (S)-3-(7-fluoro-8-(4-fluoro-2,6-dimethylphenyl)-2H,4H-spiro[benzo[b][1,4]dioxepane-3,1'-cyclopropane]-6-yl)-3-((R)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S) Preparation of 3-(7-fluoro-8-(4-fluoro-2,6-dimethylphenyl)-2H,4H-spiro[benzo[b][1,4]dioxepane-3,1'-cyclopropane]-6-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (12a and 12b)

[0348] Referring to the synthetic method of Example 11, 3-bromo-2-fluoro-5,6-dihydroxybenzaldehyde was substituted for 5-bromo-2,3-dihydroxybenzaldehyde to obtain:

[0349] 12a, white solid.

[0350] LC-MS: m / z 764.3[M+H] + .

[0351] 1 H-NMR (400MHz, CD3OD) δ9.06(d,J=8.8Hz,1H),7.89(s,1H),6.86-6.84(m,3H),6.69(d,J=5.2H z,1H),5.86-5.80(m,2H),5.50-5.39(m,1H),4.75-4.35(m,4H),4.10(d,J=8.0Hz,1H),4.00(d ,J=12.0Hz,1H),3.90-3.83(m,2H),3.55-3.44(m,2H),3.21-3.08(m,1H),2.94-2.81(m,3H),2 .22-2.03(m,4H),1.98-1.93(m,4H),1.46-1.40(m,1H),0.99-0.96(m,6H),0.75-0.66(m,4H).

[0352] 12b, white solid.

[0353] LC-MS: m / z 764.1[M+H] + .

[0354] 1H-NMR (400MHz, CD3OD) δ9.17(d,J=5.2Hz,1H),7.91(s,1H),6.92(s,1H),6.88(d,J=6.4Hz,2H),6.75( d,J=4.8Hz,1H),5.91-5.87(m,1H),5.81-5.78(m,1H),5.50-5.37(m,1H),4.75-4.40(m,4H),4.15(d, J=8.0Hz,1H),4.08(d,J=8.0Hz,1H),3.92(s,2H),3.60-3.45(m,2H),3.06-3.01(m,1H),2.93-2.84(m ,3H),2.07-2.03(m,6H),1.88-1.79(m,2H),1.41-1.35(m,1H),0.93-0.90(m,6H),0.83-0.69(m,4H).

[0355] Example 13: (S)-3-(8-(4-fluoro-2,6-dimethylphenyl)-7-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((R)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of 3-(8-(4-fluoro-2,6-dimethylphenyl)-7-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (13a and 13b)

[0356] Step 1: Preparation of 6-bromo-2,3-dihydroxybenzaldehyde (13-1).

[0357] At 0°C under a nitrogen atmosphere, 6-bromo-2-hydroxy-3-methoxybenzaldehyde (5.00 g, 21.64 mmol) was dissolved in anhydrous dichloromethane (50.0 mL). A 1 M solution of boron tribromide in dichloromethane (43.2 mL, 43.20 mmol) was slowly added. The mixture was reacted at 0°C for 1 hour. The reaction system was allowed to warm naturally and stirred for 16 hours. The mixture was concentrated under reduced pressure to give 6.04 g of the crude title compound as a brown-green solid.

[0358] LC-MS: m / z 216.9, 218.9 [M+H] + .

[0359] Step 2: Preparation of 7-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde (13-2).

[0360] Crude 3-bromo-2-fluoro-5,6-dihydroxybenzaldehyde (6.04 g), 1,3-dibromopropane (6.50 g, 32.18 mmol), and potassium carbonate (6.00 g, 43.48 mmol) were dissolved in N,N-dimethylformamide (50.0 mL) at room temperature and reacted at 80°C for 2 hours. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The filtrate was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to give 3.04 g of the title compound as a colorless oil, with a total yield of 54.6% over two steps.

[0361] LC-MS: m / z 257.3, 259.3 [M+H] + .

[0362] Step 3: Preparation of 7-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde (13-3).

[0363] 7-Bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde (3.00 g, 11.67 mmol), methylboric acid (1.40 g, 23.33 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (855 mg, 1.17 mmol) and potassium carbonate (3.23 g, 23.40 mmol) were added to 1,4-dioxane (30.0 mL) and water (6.0 mL) at room temperature under nitrogen protection and reacted at 100°C for 2 hours. The reaction was quenched with water (100 mL), extracted with ethyl acetate (100 mL x 3), and the filtrate was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to give 1.40 g of the title compound as a colorless oil in a yield of 62.2%.

[0364] LC-MS: m / z 193.1[M+H] + .

[0365] Step 4: Preparation of 8-bromo-7-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde (13-4).

[0366] 7-Methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde (1.40 g, 7.29 mmol) and N-bromosuccinimide (1.30 g, 7.29 mmol) were added to acetonitrile (20.0 mL) at room temperature and reacted at 50°C for 16 hours. The reaction was quenched with 100 mL of water and extracted with ethyl acetate (100 mL x 3). The filtrate was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to afford 1.41 g of the title compound as a colorless oil in a yield of 71.4%.

[0367] LC-MS: m / z 271.0, 273.0 [M+H] + .

[0368] Referring to the synthetic method of Example 11, 8-bromo-7-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde was substituted for 8-bromo-2H,4H-spiro[benzo[b][1,4]dioxepane-3,1'-cyclopropane]-6-carbaldehyde to obtain:

[0369] 13a, white solid.

[0370] LC-MS: m / z 734.3[M+H] + .

[0371] 1 H-NMR(400MHz,CD3OD)δ8.77(d,J=7.6Hz,1H),7.87(s,1H),6.88-6.81(m,3H),6.54(s ,1H),5.86-5.72(m,2H),5.47-5.29(m,1H),4.55-4.46(m,2H),4.41-4.26(m,3H),4.2 1-4.14(m,2H),4.10-4.04(m,1H),3.51-3.38(m,3H),3.16-3.10(m,1H),2.94-2.72(m ,3H),2.24-2.19(m,2H),2.10-1.87(m,10H),1.48-1.38(m,1H),0.99(t,J=6.8Hz,6H).

[0372] 13b, white solid.

[0373] LC-MS: m / z 734.1[M+H] + .

[0374] 1H-NMR (400MHz, CD3OD) δ8.64(d,J=8.4Hz,1H),7.86(s,1H),6.97(s,1H),6.85(d,J=9.6 Hz,2H),6.58(s,1H),5.83-5.72(m,2H),5.49-5.30(m,1H),4.57-4.45(m,3H),4.38-4.2 6(m,4H),4.16-4.10(m,1H),3.51-3.42(m,2H),3.02-2.88(m,3H),2.79-2.72(m,1H),2 .33-2.21(m,2H),2.06(s,3H),1.98-1.83(m,8H),1.40-1.33(m,1H),0.96-0.89(m,6H).

[0375] Example 14: (S)-3-(8-(4-fluoro-2,6-dimethylphenyl)-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((R)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of )-3-(8-(4-fluoro-2,6-dimethylphenyl)-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (14a and 14b)

[0376] Step 1: Preparation of 2,3-dimethoxy-4-methylbenzaldehyde (14-1).

[0377] At -80°C under a nitrogen atmosphere, 1,2-dimethoxy-3-toluene (20.00 g, 131 mol) was dissolved in anhydrous tetrahydrofuran (500.0 mL). A 2.5 M solution of n-butyllithium in tetrahydrofuran (57.0 mL, 144 mmol) was slowly added. After reacting at -80°C for 1 hour, anhydrous N,N-dimethylformamide solution (55.0 ml, 720 mmol) was slowly added. The reaction system was allowed to warm naturally and stirred for a further 2.5 hours. The mixture was then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 5%-50%) to give 16.5 g of the title compound as a colorless oil in a yield of 69.7%.

[0378] LC-MS: m / z 181.2[M+H] + .

[0379] Step 2: Preparation of 5-bromo-2,3-dimethoxy-4-methylbenzaldehyde (14-2).

[0380] 2,3-Dimethoxy-4-methylbenzaldehyde (16.50 g, 91.6 mmol) and N-bromosuccinimide (24.40 g, 137 mmol) were dissolved in dichloromethane (500.0 mL) at room temperature and allowed to react for 16 hours. Water (500 mL) was added, and the mixture was extracted with dichloromethane (500 mL x 3). The filtrate was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to obtain 18.0 g of the title compound as a colorless oil, in a yield of 75.9%.

[0381] LC-MS: m / z 259.1, 261.2 [M+H] + .

[0382] Step 3: Preparation of 5-bromo-2,3-dihydroxy-4-methylbenzaldehyde (14-3).

[0383] 5-Bromo-2,3-dimethoxy-4-methylbenzaldehyde (10.00 g, 38.6 mmol) was dissolved in anhydrous dichloromethane (500 mL) at 0°C under a nitrogen atmosphere. A 1 M solution of boron tribromide in dichloromethane (193.0 mL, 193 mmol) was slowly added to the mixture. The reaction was incubated at 0°C for 1 hour. The reaction system was allowed to warm naturally and stirred for 2.5 hours. The mixture was then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 5%-50%) to give 6.70 g of the title compound as a colorless oil in a yield of 75.1%.

[0384] LC-MS: m / z 231.0, 233.0 [M+H] + .

[0385] Step 4: Preparation of 8-bromo-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde (14-4).

[0386] At room temperature under a nitrogen atmosphere, 5-bromo-2,3-dihydroxy-4-methylbenzaldehyde (6.70 g, 29.0 mmol), 1,3-dibromopropane (16.80 g, 83.16 mmol), and diisopropylethylamine (10.7 g, 82.94 mmol) were dissolved in N,N-dimethylformamide (100 mL) and reacted at 80°C for 16 hours. The reaction was quenched with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The filtrate was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to obtain 5.20 g of the title compound as a colorless oil in a 66.1% yield.

[0387] LC-MS: m / z 271.0, 273.0 [M+H] + .

[0388] Referring to the synthetic method of Example 11, 8-bromo-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carbaldehyde was substituted for 8-bromo-2H,4H-spiro[benzo[b][1,4]dioxepane-3,1'-cyclopropane]-6-carbaldehyde to obtain:

[0389] 14a, white solid.

[0390] LC-MS: m / z 734.2[M+H] + .

[0391] 1 H-NMR(400MHz,CD3OD)δ7.82(s,1H),6.84-6.77(m,2H),6.72(s,1H),6.54(s,1 H),5.69-5.56(m,2H),5.27-5.10(m,1H),4.32-4.16(m,3H),4.12-4.06(m,1H), 3.89-3.81(m,2H),3.54-3.40(m,2H),2.88-2.62(m,6H),2.29-2.14(m,2H),2.0 7-1.91(m,6H),1.78(s,3H),1.72(s,3H),1.50-1.44(m,1H),0.99-0.94(m,6H).

[0392] 14b, white solid.

[0393] LC-MS: m / z 734.2[M+H] + .

[0394] 1H-NMR(400MHz,CD3OD)δ7.72(s,1H),6.91(s,1H),6.87(s,1H),6.84(s,1H),6.60(s,1H),5 .66-5.60(m,2H),5.40-5.35(m,1H),5.21-5.25(m,1H),4.39-4.14(m,6H),3.95-3.79(m,2 H),3.24-3.20(m,2H),2.89-2.78(m,2H),2.63-2.48(m,2H),2.36-2.19(m,2H),2.07-2.02 (m,1H),1.94(s,6H),1.84(s,3H),1.81-1.74(m,1H),1.45-1.40(m,1H),0.92-0.89(m,6H).

[0395] Example 15: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(7-fluoro-8-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(7-fluoro-8-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (15a and 15b)

[0396] Referring to the synthesis method of Example 5, (trimethylphenyl)boric acid was used instead of (2,6-dimethylphenyl)boric acid to prepare:

[0397] 15a, white solid.

[0398] LC-MS: m / z 704.3[M+H] + .

[0399] 1H-NMR (400 MHz, CD3OD) δ 9.00 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 6.90 (s, 2H), 6.86 (s, 1H), 6.64 (d, J = 7.2 Hz, 1H), 5.86 - 5.79 (m, 2H), 4.38 - 4.32 (m, 1H), 4.26 - 4.20 (m, 1H), 4.18 - 4.07 (m, 2H), 3.30 - 3.27 (m, 2H), 3.16 - 3.02 (m, 2H), 2.97 (s, 6H), 2.85 - 2.68 (m, 2H), 2.29 (s, 3H), 2.24 - 2.18 (m, 2H), 2.07 - 1.94 (m, 5H), 1.90 (s, 3H), 1.48 - 1.41 (m, 1H), 1.00 - 0.96 (m, 6H).

[0400] 15b, white solid.

[0401] LC-MS: m / z 704.1 [M+H] + .

[0402] 1 H-NMR (400 MHz, CD3OD) δ 9.10 (d, J = 7.6 Hz, 1H), 7.94 (s, 1H), 6.93 (s, 2H), 6.92 (s, 1H), 6.69 (d, J = 7.2 Hz, 1H), 5.91 - 5.86 (m, 1H), 5.78 (t, J = 8.0 Hz, 1H), 4.38 - 4.29 (m, 2H), 4.25 - 4.11 (m, 2H), 3.37 - 3.34 (m, 2H), 3.07 - 2.95 (m, 8H), 2.88 - 2.82 (m, 1H), 2.72 - 2.68 (m, 1H), 2.31 - 2.50 (m, 5H), 2.01 (s, 6H), 1.86 - 1.82 (m, 2H), 1.38 - 1.32 (m, 1H), 0.93 - 0.89 (m, 6H).

[0403] Example 16: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (16a and 16b)

[0404] Referring to the synthesis method of Example 2, (4-fluoro-2,6-dimethylphenyl)boric acid was used instead of (2,6-dimethylphenyl)boric acid to prepare:

[0405] 16a, white solid.

[0406] LC-MS: m / z 690.7[M+H] + .

[0407] 1 H-NMR(400MHz,CD3OD)δ9.15(d,J=8.0Hz,1H),7.93(s,1H),6.94(d,J=2.4Hz,1H),6.82-6 .77(m,3H),6.61(d,J=2.0Hz,1H),5.75(t,J=8.0Hz,1H),5.30-5.25(m,1H),4.18(t,J=5. 6Hz,2H),3.99(t,J=5.6Hz,2H),3.30-3.27(m,2H),3.08-2.94(m,8H),2.84-2.80(m,2H), 2.13-2.08(m,2H),1.99-1.96(m,5H),1.88(s,3H),1.52-1.44(m,1H),1.00-0.97(m,6H).

[0408] 16b, white solid.

[0409] LC-MS: m / z 690.7[M+H] + .

[0410] 1H-NMR(400MHz,CD3OD)δ9.13(d,J=8.0Hz,1H),7.95(s,1H),7.02(d,J=2.4Hz,1H),6.90(s,1H), 6.84(s,1H),6.82(s,1H),6.67(d,J=2.4Hz,1H),5.74(t,J=8.0Hz,1H),5.26(t,J=7.6Hz,1H),4 .22(t,J=4.8Hz,2H),4.04(t,J=5.6Hz,2H),3.30-3.31(m,2H),3.06-2.97(m,8H),2.84-2.81(m ,2H),2.16-2.11(m,2H),2.01(s,6H),1.87-1.83(m,2H),1.40-1.33(m,1H),0.94-0.90(m,6H).

[0411] Example 17: (S)-3-(9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-( Preparation of (S)-3-(9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S)-3-(9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (17a and 17b)

[0412] With reference to the synthetic method of Example 2, (4-fluoro-2,6-dimethylphenyl)boric acid was used instead of (2,6-dimethylphenyl)boric acid, and 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was used instead of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0413] 17a, white solid.

[0414] LC-MS: m / z 720.1[M+H] + .

[0415] 1H-NMR (400 MHz, CD3OD) δ 9.17 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.84 - 6.78 (m, 3H), 6.62 (d, J = 2.4 Hz, 1H), 5.78 - 5.74 (m, 1H), 5.52 - 5.34 (m, 1H), 5.30 - 5.26 (m, 1H), 4.70 - 4.40 (m, 4H), 4.18 (t, J = 5.6 Hz, 2H), 4.00 (t, J = 5.6 Hz, 2H), 3.51 - 3.42 (m, 2H), 2.92 - 2.80 (m, 4H), 2.14 - 2.08 (m, 2H), 2.04 - 1.94 (m, 5H), 1.89 (s, 3H), 1.50 - 1.43 (m, 1H), 1.00 - 0.97 (m, 6H).

[0416] 17b, white solid.

[0417] LC-MS: m / z 720.3 [M+H] + .

[0418] 1 H-NMR (400 MHz, CD3OD) δ 9.16 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.91 (s, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.68 (d, J = 2.4 Hz, 1H), 5.75 (t, J = 8.0 Hz, 1H), 5.53 - 5.35 (m, 1H), 5.30 - 5.26 (m, 1H), 4.70 - 4.40 (m, 4H), 4.23 (t, J = 5.6 Hz, 2H), 4.04 (t, J = 5.6 Hz, 2H), 3.54 - 3.48 (m, 2H), 2.93 - 2.78 (m, 4H), 2.18 - 2.12 (m, 2H), 2.01 (s, 6H), 1.89 - 1.83 (m, 2H), 1.40 - 1.33 (m, 1H), 0.92 (dd, J = 8.4, 6.8 Hz, 6H).

[0419] Example 18: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-mesotrimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-mesotrimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (18a and 18b)

[0420] Referring to the synthesis method of Example 2, (2,6-dimethylphenyl)boric acid was replaced with (mesitylene)boric acid to obtain:

[0421] 18a, white solid.

[0422] LC-MS: m / z 686.7[M+H] + .

[0423] 1 H-NMR (400MHz, CD3OD) δ7.88 (s, 1H), 6.94-6.82 (m, 4H), 6.61 (d, J = 6.0Hz, 1H), 5 .71-5.67(m,1H),5.24(t,J=7.6Hz,1H),4.16(t,J=5.6Hz,2H),3.97(t,J=6.4Hz ,2H),3.08-2.89(m,4H),2.81(s,1H),2.72-2.67(m,7H),2.30(s,3H),2.13-2.0 8(m,2H),2.00-1.93(m,6H),1.86(s,3H),1.48-1.41(m,1H),0.98-0.94(m,6H).

[0424] 18b, white solid.

[0425] LC-MS: m / z 686.7[M+H] + .

[0426] 1H-NMR (400MHz, CD3OD) δ7.83 (s, 1H), 6.98 (d, J = 2.4Hz, 1H), 6.90-6.89 (m, 3H), 6.65 (d, J = 2. 4Hz,1H),5.61(t,J=7.6Hz,1H),5.37-5.34(m,1H),4.20(t,J=5.6Hz,2H),4.00(t,J=5.6Hz,2 H),3.28-3.14(m,2H),2.98(t,J=6.8Hz,2H),2.80(s,6H),2.62-2.48(m,2H),2.30(s,3H),2. 14-2.09(m,2H),2.02-1.95(m,7H),1.75-1.68(m,1H),1.44-1.40(m,1H),0.93-0.90(m,6H).

[0427] Example 19: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(4-fluoro-2,6-dimethylphenyl)-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(4-fluoro-2,6-dimethylphenyl)-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (19a and 19b)

[0428] Referring to the synthetic method of Example 5, 8-bromo-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carboxaldehyde was used instead of 8-bromo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepane-6-carboxaldehyde.

[0429] 19a, white solid.

[0430] LC-MS: m / z 704.2[M+H] + .

[0431] 19b, white solid.

[0432] LC-MS: m / z 704.2[M+H] + .

[0433] 1H-NMR (400MHz, CD3OD) δ8.99(d,J=8.0Hz,1H),7.94(s,1H),6.90-6.85(m,3H),6.61(s,1H),5.75-5.71(m,1H),5.63-5.58(m,1H),4.36-4.16( m,4H),3.42-3.35(m,2H),3.05-2.99(m,7H),2.82-2.74(m,2H),2.27- 2.23(m,3H),2.10-1.73(m,11H),1.39-1.36(m,1H),0.90-0.87(m,6H).

[0434] Example 20: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (20a and 20b)

[0435] Step 1: Preparation of 3-bromo-6-fluoro-2-hydroxybenzaldehyde (20-1).

[0436] At room temperature and under a nitrogen atmosphere, magnesium chloride (20.04 g, 211 mmol) and paraformaldehyde (9.39 g, 313 mmol) were dissolved in anhydrous tetrahydrofuran (500.0 mL). Triethylamine (29.2 mL, 211 mmol) was slowly added. After reacting at room temperature for 10 minutes, 2-bromo-5-fluorophenol (20.06 g, 105 mmol) was added. The reaction system was transferred to 70°C and refluxed with stirring for 2.5 hours. The mixture was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 5%-50%) to obtain 24.97 g of the title crude product compound as a colorless oil.

[0437] LC-MS: m / z 219.0, 221.0 [M+H] + .

[0438] Step 2: Preparation of 3-bromo-6-fluorobenzene-1,2-diol (20-2).

[0439] At room temperature under a nitrogen atmosphere, 3-bromo-6-fluoro-2-hydroxybenzaldehyde (24.97 g, 114 mmol) was dissolved in 1N NaOH solution (137.0 mL). A 30% H₂O₂ solution (25.7 mL, 239 mmol) was added dropwise while controlling the reaction system below 50°C. The reaction system was allowed to return to room temperature and stirred for 2.5 hours. The reaction was quenched with saturated NaHSO₃ solution (250 mL) and extracted with ether (250 mL x 3). The filtrate was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to afford 12.68 g of the title compound as a colorless oil in a 53.7% yield.

[0440] LC-MS: m / z 207.1, 209.0 [M+H] + .

[0441] Step 3: Preparation of 6-bromo-9-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepane (20-3).

[0442] At room temperature under a nitrogen atmosphere, 3-bromo-6-fluorobenzene-1,2-diol (12.68 g, 61.26 mmol), 1,3-dibromopropane (36.97 g, 183 mmol), and diisopropylethylamine (23.61 g, 183 mmol) were dissolved in N,N-dimethylformamide (100.0 mL) and reacted at 80°C for 2 hours. The reaction was quenched with water (250 mL) and extracted with ethyl acetate (250 mL x 3). The filtrate was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to obtain 7.20 g of the title compound as a colorless oil in a 47.6% yield.

[0443] LC-MS: m / z 247.1, 249.1 [M+H] + .

[0444] Step 4: Preparation of 9-bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepane-7-carbaldehyde (20-4).

[0445] At -80°C under a nitrogen atmosphere, 6-bromo-9-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepane (7.20 g, 29.15 mmol) was dissolved in anhydrous tetrahydrofuran (500.0 mL). A 2.5 M solution of n-butyllithium in tetrahydrofuran (12.8 mL, 32.00 mmol) was slowly added. After reacting at -80°C for 1 hour, anhydrous N,N-dimethylformamide solution (13.6 ml, 145 mmol) was slowly added. The reaction system was allowed to warm naturally and stirred for a further 2.5 hours. The mixture was then concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 5%-50%) to give 6.20 g of the title compound as a colorless oil in a yield of 77.5%.

[0446] LC-MS: m / z 275.1, 276.1 [M+H] + .

[0447] Referring to the synthesis method of Example 2, 9-bromo-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepane-7-carboxaldehyde was substituted for 9-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepane-7-carboxaldehyde to obtain:

[0448] 20a, white solid.

[0449] LC-MS: m / z 690.2[M+H] + .

[0450] 1 H-NMR(400MHz,CD3OD)δ9.18(d,J=7.6Hz,1H),7.92(s,1H),7.12-7.00(m,3H),6.75( s,1H),6.62(d,J=7.6Hz,1H),5.72(t,J=8.0Hz,1H),5.58-5.53(m,1H),4.25-4.22(m, 2H),4.03-4.00(m,2H),3.32-3.27(m,2H),3.02-2.98(m,8H),2.85-2.82(m,2H),2.1 6-2.14(m,2H),2.01-1.93(m,5H),1.77(s,3H),1.51-1.47(m,1H),1.00-0.96(m,6H).

[0451] 20b, white solid.

[0452] LC-MS: m / z 690.2[M+H] + .

[0453] 1H-NMR(400MHz,CD3OD)δ9.18(d,J=8.0Hz,1H),7.95(s,1H),7.16-7.07(m,3H),6.90( s,1H),6.66(d,J=7.6Hz,1H),5.74(t,J=7.6Hz,1H),5.58-5.53(m,1H),4.30-4.27(m, 2H),4.08-4.05(m,2H),3.27-3.22(m,2H),3.01-2.99(m,8H),2.84-2.81(m,2H),2.2 2-2.17(m,2H),2.00(s,6H),1.84-1.81(m,2H),1.37-1.32(m,1H),0.90-0.87(m,6H).

[0454] Example 21: Preparation of (S)-3-((R)-2-(5-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (21a and 21b)

[0455] Step 1: Preparation of methyl 4-methyl-2-(2-oxo-4-(trifluoromethyl)-5-vinylpyridin-1(2H)-yl)pentanoate (Compound 21-1).

[0456] To a solution of methyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (3.00 g, 8.11 mmol) and tri-n-butylvinyltin (3.85 g, 12.14 mmol) in 1,4-dioxane (30.0 mL) at room temperature under a nitrogen atmosphere was added bis(tri-tert-butylphosphine)palladium (414 mg, 0.81 mmol). The reaction mixture was purged with N2 three times and stirred at 100°C for 4 hours. The reaction was quenched with saturated potassium fluoride solution (500 mL) and extracted with ethyl acetate (250 mL x 3). The filtrate was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 15%-35%) to afford 2.15 g of the title compound as a yellow oil in an 83.6% yield.

[0457] LC-MS: m / z 318.3 [M+H] + .

[0458] Step 2: Preparation of methyl 2-(5-formyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (Compound 21-2).

[0459] To a solution of methyl 4-methyl-2-(2-oxo-4-(trifluoromethyl)-5-vinylpyridin-1(2H)-yl)pentanoate (1.49 g, 4.70 mmol) in 1,4-dioxane (15.0 mL) and water (4.5 mL) at room temperature were added potassium osmate dihydrate (210 mg, 0.47 mmol) and sodium periodate (2.00 g, 9.34 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, the filtrate diluted with water (250 mL), and extracted with ethyl acetate (250 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford 462 mg of the title compound as a yellow oil, in a 30.8% yield.

[0460] LC-MS: m / z 320.3[M+H] + .

[0461] Step 3: Preparation of methyl 2-(5-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (Compound 21-3).

[0462] To a solution of dimethylamine hydrochloride (335 mg, 4.11 mmol) in 1,2-dichloroethane (8.0 mL) at room temperature under a nitrogen atmosphere were added triethylamine (552 mg, 5.46 mmol), acetic acid (0.47 mL, 8.21 mmol), and methyl 2-(5-formyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (437 mg, 1.37 mmol). The reaction system was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (580 mg, 2.74 mmol) was added, and the reaction system was stirred at room temperature for 4 hours. The reaction solution was diluted with methanol (20 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane = 0%-15%) to afford 386 mg of the title compound as a yellow oil in an 81.0% yield.

[0463] LC-MS: m / z 349.3[M+H] + .

[0464] Step 4: Preparation of 2-(5-(dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (Compound 21-4).

[0465] To a solution of methyl 2-(5-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (310 mg, 0.89 mmol) in methanol (8.0 mL) was added dropwise 4M lithium hydroxide (1.1 mL, 4.40 mmol) at room temperature under a nitrogen atmosphere. The reaction system was stirred at room temperature for 3 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, and the mixture was concentrated under reduced pressure to afford 396 mg of the title compound as a colorless oil, which was used directly in the next step.

[0466] LC-MS: m / z 335.3 [M+H] + .

[0467] Referring to the synthesis method of Example 1, 2-(5-(dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0468] 21a, white solid.

[0469] LC-MS: m / z 658.1[M+H] + .

[0470] 1 H-NMR(400MHz,CD3OD)δ9.13(d,J=8.0Hz,1H),8.24(s,1H),7.11-7.00(m,3H),6.83(s,1H) ),6.71(d,J=2.0Hz,1H),6.62(d,J=2.0Hz,1H),5.78(dd,J=10.0,6.4Hz,1H),5.65-5.59( m,1H),4.29(s,2H),4.26-4.10(m,4H),2.95(s,6H),2.87-2.82(m,1H),2.78-2.72(m,1H) ,2.25-2.16(m,2H),2.05-1.94(m,5H),1.83(s,3H),1.51-1.42(m,1H),0.99-0.94(m,6H).

[0471] 21b, white solid.

[0472] LC-MS: m / z 658.1[M+H] + .

[0473] 1 H-NMR(400MHz,CD3OD)δ9.08(d,J=8.0Hz,1H),8.25(s,1H),7.13-7.05(m,3H),6.95(s ,1H),6.71(d,J=2.0Hz,1H),6.68(d,J=2.0Hz,1H),5.80(t,J=8.0Hz,1H),5.67-5.61(m ,1H),4.36-4.22(m,5H),4.20-4.14(m,1H),2.96(s,6H),2.84-2.73(m,2H),2.28-2.17 (m,2H),2.01(d,J=1.2Hz,6H),187-1.84(m,2H),1.40-1.30(m,1H),0.88-0.86(m,6H).

[0474] Example 22: Preparation of (S)-3-((R)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (22a and 22b)

[0475] Step 1: Preparation of methyl 2-(5-(3-(dimethylamino)prop-1-yn-1-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (Compound 22-1).

[0476] To a solution of methyl (5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (3.00 g, 8.11 mmol) and N,N-dimethylprop-2-yn-1-amine (876 mg, 10.55 mmol) in N,N-dimethylformamide (22.5 mL) were added triethylamine (1.64 g, 16.23 mmol), bis(tetrakistriphenylphosphine)palladium dichloride (569 mg, 0.81 mmol) and cuprous iodide (309 mg, 1.62 mmol) at room temperature in a sealed tube. The reaction solution was replaced with N2 three times and stirred at 60°C for 16 hours. The reaction solution was filtered, and the filtrate was diluted with water (500 mL). The product was extracted with ethyl acetate (500 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate:petroleum ether = 65%-95%) to give 2.11 g of the title compound as a yellow oil in a yield of 69.9%.

[0477] LC-MS: m / z 373.2[M+H] + .

[0478] Step 2: Preparation of methyl 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (Compound 22-2).

[0479] To a solution of methyl 2-(5-(3-(dimethylamino)prop-1-yn-1-yl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (2.10 g, 5.64 mmol) in ethanol (20.0 mL) was added 10% palladium on carbon (2.00 g) at room temperature. The reaction mixture was purged with H₂ three times and then stirred under hydrogen (15 psi) at room temperature for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: methanol / dichloromethane = 0%-7%) to afford 600 mg of the title compound as a yellow oil, in a yield of 28.3%.

[0480] LC-MS: m / z 377.4 [M+H] + .

[0481] Step 3: Preparation of 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid (Compound 22-3).

[0482] To a solution of methyl 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoate (280 mg, 0.74 mmol) in methanol (3.0 mL) was added dropwise 4M lithium hydroxide (0.93 mL, 3.72 mmol) at room temperature under a nitrogen atmosphere. The reaction system was stirred at room temperature for 2 hours. 1N hydrochloric acid was added dropwise to adjust the pH to 6-7, and the mixture was concentrated under reduced pressure to afford 270 mg of the title compound as a colorless oil, which was used directly in the next step.

[0483] LC-MS: m / z 263.3[M+H] + .

[0484] Referring to the synthesis method of Example 1, 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was used instead of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0485] 22a, white solid.

[0486] LC-MS: m / z 686.1[M+H] + .

[0487] 22b, white solid.

[0488] LC-MS: m / z 686.1[M+H] + .

[0489] 1 H-NMR(400MHz,CD3OD)δ9.03(d,J=8.0Hz,1H),7.85(s,1H),7.14-7.05(m,3H),6.86( s,1H),6.72(d,J=2.0Hz,1H),6.68(d,J=2.4Hz,1H),5.78-5.74(m,1H),5.68-5.62(m, 1H),4.30-4.16(m,4H),3.22-3.15(m,3H),2.91(s,6H),2.75-2.62(m,4H),2.24-2.1 9(m,2H),2.06-1.96(m,7H),1.87-1.75(m,2H),1.36-1.34(m,1H),0.87-0.85(m,6H).

[0490] Example 23: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (23a and 23b)

[0491] Step 1: Preparation of methyl 2-(5-bromo-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (Compound 23-1).

[0492] 5-Bromo-4-methylpyridin-2(1H)-one (5.00 g, 26.60 mmol), methyl 2-bromo-4-methylpentanoate (8.34 g, 39.90 mmol), and potassium carbonate (7.35 g, 53.26 mmol) were added to N,N-dimethylformamide (50.0 mL) at room temperature and reacted at 70°C for 16 hours. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-10%) to obtain 4.72 g of the title compound as a light yellow solid in a 56.1% yield.

[0493] LC-MS: m / z 315.8, 317.8 [M+H] + .

[0494] With reference to the synthesis method of Example 7, 2-(5-bromo-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate was substituted for 2-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazine-1(6H)-yl)-4-methylpentanoate to obtain:

[0495] 23a, white solid.

[0496] LC-MS: m / z 618.2[M+H] + .

[0497] 1H-NMR(400MHz,CD3OD)δ7.55(s,1H),7.15-7.06(m,3H),6.61(s,2H),6.36(s,1H),5 .60-5.51(m,2H),4.34-4.28(m,3H),4.17-4.12(m,1H),3.12-3.07(m,1H),3.05-2. 98(m,1H),2.84(t,J=7.2Hz,2H),2.68(s,6H),2.64-2.56(m,2H),2.26-2.16(m,5H) ,2.01(s,3H),1.98-1.94(m,2H),1.93(s,3H),1.48-1.38(m,1H),0.96-0.91(m,6H).

[0498] 23b, white solid.

[0499] LC-MS: m / z 618.2[M+H] + .

[0500] 1 H-NMR (400MHz, CD3OD) δ7.53 (s, 1H), 7.16-7.06 (m, 3H), 6.68 (d, J = 2.4Hz, 1H), 6.66 (d, J = 2. 0Hz,1H),6.46(s,1H),5.63-5.59(m,2H),4.36-4.16(m,4H),3.37-3.30(m,1H),3.23-3.16(m ,1H),2.95-2.91(m,2H),2.84(s,6H),2.59-2.55(m,1H),2.49-2.43(m,1H),2.28-2.18(m,5 H),2.02(s,6H),2.00-1.94(m,1H),1.86-1.79(m,1H),1.44-1.37(m,1H),0.92-0.89(m,6H).

[0501] Example 24: Preparation of (S)-3-(8-(2,6-diethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S)-3-(8-(2,6-diethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (24a and 24b)

[0502] Step 1: Preparation of (2,6-diethylphenyl)boronic acid (Compound 24-1).

[0503] At -78°C under a nitrogen atmosphere, 2-bromo-1,3-diethylbenzene (1.50 g, 7.04 mmol) was dissolved in tetrahydrofuran (25.0 mL). A 2.5 M solution of n-butyllithium in n-hexane (3.6 mL, 8.80 mmol) was added dropwise. The mixture was allowed to react at -78°C for 1 hour. Trimethyl borate (1.46 g, 14.04 mmol) was then added dropwise, and the reaction continued at room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-20%) to afford 1.19 g of the title compound as a white solid in a 94.9% yield.

[0504] LC-MS: m / z 179.0 [M+H] + .

[0505] Referring to the synthesis method of Example 1, (2,6-diethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to obtain:

[0506] 24a, white solid.

[0507] LC-MS: m / z 700.2[M+H] + .

[0508] 1 H-NMR (400MHz, CD3OD) δ7.88(s,1H),7.18(t,J=7.6Hz,1H),7.08-7.02(m,2H),6.76(s,1H),6.70(d,J=2 .0Hz,1H),6.61(d,J=2.4Hz,1H),5.67(t,J=8.0Hz,1H),5.62-5.59(m,1H),4.34-4.21(m,3H),4.14-4.0 8(m,1H),3.12-2.89(m,4H),2.71(s,6H),2.70-2.60(m,2H),2.30(q,J=7.6Hz,2H),2.26-2.09(m,4H),1 .96(t,J=7.6Hz,2H),1.45-1.38(m,1H),0.99(t,J=7.6Hz,3H),0.95-0.90(m,6H),0.83(t,J=7.5Hz,3H).

[0509] 24b, white solid.

[0510] LC-MS: m / z 700.2[M+H] + .

[0511] 1 H-NMR (400MHz, CD3OD) δ7.78 (s, 1H), 7.22-7.18 (m, 1H), 7.09-7.07 (m, 2H), 6.90 (s, 1H), 6.73 (d, J = 2.4Hz, 1H), 6.6 6(d,J=2.0Hz,1H),5.70(dd,J=10.8Hz,4.0Hz,1H),5.59(t,J=7.6Hz,1H),4.38-4.23(m,3H),4.19-4.13(m,1H),3. 28-3.18(m,2H),3.00(t,J=6.8Hz,2H),2.82(s,6H),2.60-2.56(m,1H),2.47-2.41(m,1H),2.34-2.21(m,6H),2.01 -1.94(m,1H),1.72-1.65(m,1H),1.42-1.35(m,1H),0.99(td,J=7.2Hz,2.0Hz,6H),0.87(dd,J=6.8Hz,2.0Hz,6H).

[0512] Example 25: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-4-methoxy-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methoxy-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (25a and 25b)

[0513] Step 1: Preparation of 5-bromo-4-fluoropyridin-2-amine (Compound 25-1).

[0514] 4-Fluoropyridin-2-amine (5.00 g, 44.64 mmol) was dissolved in acetonitrile (50.0 mL), and N-bromosuccinimide (9.50 g, 53.6 mmol) was added. The mixture was reacted at room temperature for 4 hours and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to obtain 7.20 g of the title compound as a yellow solid in a yield of 84.9%.

[0515] LC-MS: m / z 191.0, 193.0 [M+H] + .

[0516] Step 2: Preparation of 5-bromo-4-fluoropyridin-2(1H)-one (Compound 25-2).

[0517] 5-Bromo-4-fluoropyridin-2-amine (6.00 g, 31.41 mmol) was dissolved in concentrated sulfuric acid (12.0 mL) and water (60.0 mL) at 0°C. Sodium nitrite (2.60 g, 37.68 mmol) was added and the mixture was allowed to react at room temperature for 2 hours. The pH of the reaction was adjusted to neutral with saturated aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-25%) to obtain 6.00 g of the title compound as a light yellow solid in a 99.5% yield.

[0518] LC-MS: m / z 192.0, 194.0 [M+H] + .

[0519] Step 3: Preparation of methyl 2-(5-bromo-4-fluoro-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (Compound 25-3).

[0520] 5-Bromo-4-fluoropyridin-2(1H)-one (6.00 g, 31.25 mmol), methyl 2-bromo-4-methylpentanoate (9.80 g, 46.88 mmol), and potassium carbonate (8.60 g, 62.32 mmol) were added to N,N-dimethylformamide (30 mL) at room temperature and reacted at 70°C for 18 hours. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The filtrate was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-80%) to obtain 3.43 g of the title compound as a light yellow solid in a 34.3% yield.

[0521] LC-MS: m / z 320.0, 322.0 [M+H] + .

[0522] Step 4: Preparation of (E)-methyl 2-(5-(2-ethoxyvinyl)-4-fluoro-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (Compound 25-4).

[0523] At room temperature and under nitrogen atmosphere, methyl 2-(5-bromo-4-fluoro-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (5.70 g, 17.81 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (5.80 g, 29.29 mmol), tetrakis(triphenylphosphine)palladium (1.86 g, 1.61 mmol), and potassium carbonate (4.40 g, 31.88 mmol) were added to a mixed solvent of dioxane (60.0 mL) and water (15.0 mL). The mixture was reacted at 100° C. for 1 hour, and the reaction was quenched with water (50 mL). Ethyl acetate (50 mL x 10 mL) was added to the mixture. 3) Extraction, the filtrate was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-50%) to obtain 4.09 g of the title compound as a yellow solid, in a yield of 73.6%.

[0524] LC-MS: m / z 312.0 [M+H] + .

[0525] Step 5: Preparation of methyl 2-(4-fluoro-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (Compound 25-5).

[0526] Methyl (E)-2-(5-(2-ethoxyvinyl)-4-fluoro-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (6.76 g, 21.73 mmol) and trifluoroacetic acid (20.0 mL) were added to dichloromethane (70.0 mL) at room temperature and allowed to react for 16 hours. The mixture was concentrated under reduced pressure to afford 6.13 g of the crude title compound as a brown oil, which was used directly in the next reaction.

[0527] LC-MS: m / z 284.0 [M+H] + .

[0528] Step 6: Preparation of methyl 2-(5-(2-(dimethylamino)ethyl)-4-fluoro-2-oxopyridin-1(2H)yl)-4-methylpentanoate (Compound 25-6).

[0529] The crude product of methyl 2-(4-fluoro-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate (3.13 g) and dimethylamine hydrochloride (2.61 g, 32.4 mmol) were added to 1,2-dichloroethane (50.0 mL) at room temperature and reacted for 2 hours. Sodium triacetoxyborohydride (4.49 g, 21.18 mmol) was added and reacted for 16 hours at room temperature. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-50%) to obtain 1.31 g of the title compound as a yellow solid, with a total yield of 19.3% over two steps.

[0530] LC-MS: m / z 313.2[M+H] + .

[0531] Step 7: Preparation of 2-(5-(2-(dimethylamino)ethyl)-4-methoxy-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid (Compound 25-7).

[0532] Methyl 2-(5-(2-(dimethylamino)ethyl)-4-fluoro-2-oxopyridin-1(2H)yl)-4-methylpentanoate (900 mg, 2.88 mmol) and lithium hydroxide monohydrate (346 mg, 8.24 mmol) were added to methanol (6.0 mL) and water (2.0 mL) at room temperature and allowed to react for 16 hours. The reaction mixture was adjusted to pH 6-7 with 1N hydrochloric acid and concentrated under reduced pressure to afford 1.12 g of the crude title compound as a yellow solid, which was used directly in the next reaction.

[0533] LC-MS: m / z 311.2 [M+H] + .

[0534] Referring to the synthesis method of Example 1, 2-(5-(2-(dimethylamino)ethyl)-4-methoxy-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid was used instead of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0535] 25a, white solid.

[0536] LC-MS: m / z 634.3[M+H] + .

[0537] 1H-NMR (400MHz, CD3OD) δ8.92(d,J=8.2Hz,1H),7.62(s,1H),7.12-7.01(m,3H),6.66(d,J=2 .0Hz,1H),6.62(d,J=2.1Hz,1H),5.86(s,1H),5.72-5.62(m,2H),4.30-4.21(m,3H),4.16-4 .10(m,1H),3.88(s,3H),3.29-3.24(m,2H),2.94(s,6H),2.87-2.73(m,4H),2.27-2.16(m, 2H), 2.00 (s, 3H), 1.92 (t, J = 7.6Hz, 2H), 1.83 (s, 3H), 1.49-1.42 (m, 1H), 0.98-0.94 (m, 6H).

[0538] 25b, white solid.

[0539] LC-MS: m / z 634.3[M+H] + .

[0540] 1 H-NMR (400MHz, CD3OD) δ8.86 (d, J=8.0Hz, 1H), 7.62 (s, 1H), 7.12-7.04 (m, 3H) ,6.70(d,J=2.0Hz,2H),6.67(d,J=2.0Hz,2H),5.97(s,1H),5.68-5.60(m,2H) ,4.34-4.14(m,4H),3.88(s,3H),2.93(s,6H),2.91-2.74(m,4H),2.29-2.18( m,2H),2.00(s,6H),1.84-1.71(m,2H),1.36-1.28(m,1H),0.85-0.84(m,6H).

[0541] Example 26: Preparation of (S)-3-((R)-2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (26a and 26b)

[0542] Step 1: Preparation of 5-bromo-4-(difluoromethyl)-2-methoxypyridine (Compound 26-1).

[0543] At -78°C under a nitrogen atmosphere, 5-bromo-2-methoxyisonicotinaldehyde (5.00 g, 23.15 mmol) was dissolved in 1,2-dichloroethane (100.0 ml). Diethylaminosulfur trifluoride (7.49 g, 46.52 mmol) was added dropwise and stirred overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 4:1). 5.39 g of the title compound was obtained, with a yield of 97.8%.

[0544] LC-MS: m / z 238.0, 240.0 [M+H] + .

[0545] Step 2: Preparation of 5-bromo-4-(difluoromethyl)pyridin-2(1H)-one (Compound 26-2).

[0546] At room temperature under a nitrogen atmosphere, 5-bromo-4-(difluoromethyl)-2-methoxypyridine (5.39 g, 22.65 mmol) was dissolved in acetonitrile (200.0 ml). Trimethylsilyl chloride (7.41 g, 68.29 mmol) and sodium iodide (10.20 g, 68.00 mmol) were added, and the mixture was heated to 65°C and allowed to react overnight. Hydrazine hydrate (10.5 g, 0.21 mol) was added dropwise under an ice bath, stirred for 30 minutes, and then heated to 80°C and allowed to react overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1). 4.89 g of the title compound was obtained, with a yield of 96.6%.

[0547] LC-MS: m / z 224.0, 226.0 [M+H] + .

[0548] Step 3: Preparation of methyl 2-(5-bromo-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (Compound 26-3).

[0549] 5-Bromo-4-(difluoromethyl)pyridin-2(1H)-one (4.89 g, 21.83 mmol), methyl 2-bromo-4-methylpentanoate (5.62 g, 26.86 mmol), potassium carbonate (6.20 g, 44.84 mmol), and N,N-dimethylformamide (50.0 ml) were added to a reaction flask at room temperature and heated to 70°C overnight. The reaction mixture was filtered, extracted with water (200 ml) and ethyl acetate (200 ml), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 4:1). 2.40 g of the title compound was obtained, with a yield of 30.5%.

[0550] LC-MS: m / z 352.0, 354.0 [M+H] + .

[0551] With reference to the synthesis method of Example 7, 2-(5-bromo-4-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate was substituted for 2-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoate to obtain:

[0552] 26a, white solid.

[0553] LC-MS: m / z 654.3[M+H] + .

[0554] 1 H-NMR(400MHz,DMSO-d6)δ8.85(d,J=8.4Hz,1H),7.66(s,1H),7.15-7.03(m,4H ),6.70(d,J=2.4Hz,1H),6.60(d,J=2.0Hz,1H),6.47(s,1H),5.61-5.50(m,2H), 4.18-4.05(m,4H),2.68-2.56(m,2H),2.41-2.34(m,2H),2.19(s,6H),2.10-2.0 5(m,2H),1.96(s,3H),1.91-1.70(m,7H),1.35-1.28(m,1H),0.88-0.77(m,6H).

[0555] 26b, white solid.

[0556] LC-MS: m / z 654.3[M+H] + .

[0557] 1H-NMR(400MHz,DMSO-d6)δ8.95(br,1H),7.66(s,1H),7.15-7.00(m,4H),6.70(d,J=2.0Hz ,1H),6.61(d,J=2.0Hz,1H),6.55(s,1H),5.58-5.52(m,2H),4.23-4.05(m,4H),2.67-2.5 6(m,2H),2.43-2.30(m,2H),2.33-2.32(m,1H),2.19(s,6H),2.13-2.12(m,2H),1.96(d,J =2.0Hz,6H),1.76-1.70(m,1H),1.65-1.58(m,1H),1.22-1.14(m,2H),0.73-0.72(m,6H).

[0558] Example 27: Preparation of (S)-3-(8-(2,6-dichlorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S)-3-(8-(2,6-dichlorophenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (27a and 27b)

[0559] Referring to the synthesis method of Example 1, (2,6-dichlorophenyl)boric acid was used instead of (2,6-dimethylphenyl)boric acid to prepare:

[0560] 27a, white solid.

[0561] LC-MS: m / z 713.2[M+H] + .

[0562] 1H-NMR(400 MHz, CD3OD) δ 9.16 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 7.47 - 7.30 (m, 3H), 6.78 - 6.72 (m, 3H), 5.79 - 5.75 (m, 1H), 5.66 - 5.60 (m, 1H), 4.35 - 4.23 (m, 3H), 4.19 - 4.13 (m, 1H), 3.29 - 3.25 (m, 2H), 3.04 - 2.96 (m, 7H), 2.90 - 2.85 (m, 1H), 2.78 - 2.71 (m, 1H), 2.39 - 2.16 (m, 2H), 2.05 - 1.87 (m, 2H), 1.55 - 1.48 (m, 1H), 1.38 - 1.32 (m, 1H), 1.01 - 0.97 (m, 6H).

[0563] 27b, white solid.

[0564] LC-MS: m / z 713.2 [M + H] + .

[0565] 1 H-NMR(400 MHz, CD3OD) δ 9.11 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.50 - 7.47 (m, 2H), 7.34 (t, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 5.7 - 5.73 (m, 1H), 5.71 - 5.67 (m, 1H), 4.41 - 4.27 (m, 3H), 4.24 - 4.18 (m, 1H), 3.38 - 3.34 (m, 2H), 3.06 - 2.98 (s, 7H), 2.84 - 2.73 (m, 2H), 2.31 - 2.19 (m, 2H), 1.95 - 1.78 (m, 2H), 1.42 - 1.31 (m, 2H), 0.91 - 0.88 (m, 6H).

[0566] Example 28: (S)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((R)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of 3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (28a and 28b)

[0567] Referring to the synthetic method of Example 1, 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was used instead of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0568] 28a, white solid.

[0569] LC-MS: m / z 701.7[M+H] + .

[0570] 1 H-NMR (400MHz, CD3OD) δ7.84 (s, 1H), 7.12-7.00 (m, 3H), 6.72 (s, 1H), 6.66 (d, J = 2.0Hz, 1H ),6.62(d,J=2.0Hz,1H),5.72-5.61(m,2H),5.38-5.27(m,1H),4.33-4.20(m,3H),4.14-4. 08(m,1H),3.96-3.86(m,2H),3.63-3.48(m,2H),2.92(t,J=7.6Hz,2H),2.85-2.65(m,4H) ,2.29-2.13(m,2H),2.08-1.93(m,5H),1.80(s,3H),1.42-1.51(m,1H),0.90-1.00(m,6H).

[0571] 28b, white solid.

[0572] LC-MS: m / z 701.7[M+H] + .

[0573] 1H-NMR (400MHz, CD3OD) δ7.74 (s, 1H), 7.12-7.06 (m, 3H), 6.92 (s, 1H), 6.72 (d, J = 2.0Hz ,1H),6.68(d,J=2.0Hz,1H),5.70-5.64(m,2H),5.40-5.22(m,1H),4.41-4.14(m,6H),4 .01-3.83(m,2H),3.25(t,J=6.4Hz,2H),2.87-2.81(m,2H),2.66-2.54(m,2H),2.34-2. 16(m,2H),2.06-1.92(m,7H),1.81-1.74(m,1H),1.46-1.37(m,1H),0.83-0.98(m,6H).

[0574] Example 29: (S)-3-((R)-2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S Preparation of )-3-((S)-2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (29a and 29b)

[0575] Referring to the synthetic method of Example 1, 2-(5-(2-(3,3-difluoroazetidine-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was used instead of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to prepare:

[0576] 29a, white solid.

[0577] LC-MS: m / z 720.2[M+H] + .

[0578] 1H-NMR(400MHz,CD3OD)δ7.83(s,1H),7.10-7.02(m,2H),6.98-6.96(m,1H),6.66(s, 1H),6.64(d,J=2.4Hz,1H),6.58(d,J=2.0Hz,1H),5.73-5.69(m,1H),5.61-5.58(m,1 H),4.32-4.15(m,3H),4.11-4.05(m,1H),3.67-3.58(m,4H),2.84-2.52(m,6H),2.27 -2.12(m,2H),2.04-1.93(m,6H),1.74(s,3H),1.51-1.41(m,1H),0.98-0.92(m,6H).

[0579] 29b, white solid.

[0580] LC-MS: m / z 720.2[M+H] + .

[0581] 1 H-NMR (400MHz, CD3OD) δ7.84 (s, 1H), 7.12-7.04 (m, 3H), 6.82 (s, 1H), 6.72 (d, J = 2.0 Hz,1H),6.65(d,J=2.0Hz,1H),5.72-5.68(m,1H),5.64-5.60(m,1H),4.38-4.33(m,1 H),4.23-4.30(m,2H),4.11-4.17(m,1H),3.73-3.60(m,4H),2.86-2.58(m,6H),2.30 -2.17(m,2H),2.01(s,6H),1.90-1.77(m,2H),1.34-1.33(m,2H),0.87-0.84(m,6H).

[0582] Example 30: (S)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((R)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of 3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (30a and 30b)

[0583] Referring to the synthetic method of Example 20, 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to produce:

[0584] 30a, white solid.

[0585] LC-MS: m / z 720.2[M+H] + .

[0586] 1 H-NMR (400MHz, CD3OD) δ7.91 (s, 1H), 7.14-7.01 (m, 3H), 6.76 (s, 1H), 6.63 (d, J = 8.0Hz, 1H ),5.74(t,J=8.0Hz,1H),5.59-5.55(m,1H),4.67-4.40(m,5H),4.24(t,J=5.6Hz,2H),4.03 -4.00(m,2H),3.51-3.46(m,2H),2.92-2.83(m,3H),2.23-2.15(m,3H),2.07-2.03(m,1H) ,1.99-1.95(m,4H),1.79(s,2H),1.64-1.60(m,1H),1.49-1.43(m,1H),0.95-1.00(m,6H).

[0587] 30b, white solid.

[0588] LC-MS: m / z 720.2[M+H] + .

[0589] 1H-NMR (400MHz, CD3OD) δ7.76 (s, 1H), 7.15-7.07 (m, 3H), 6.88 (s, 1H), 6.66 (d, J=7 .6Hz,1H),5.66-5.61(m,2H),4.30-4.23(m,4H),4.08-4.05(m,2H),3.98-3.88(m ,2H),3.23(t,J=6.4Hz,2H),2.89-2.74(m,2H),2.69-2.56(m,2H),2.21-2.16(m, 2H),2.06-1.91(m,8H),1.76-1.71(m,1H),1.44-1.37(m,1H),0.91-0.89(m,6H).

[0590] Example 31: Preparation of (S)-3-((R)-2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (21a and 21b)

[0591] Referring to the synthesis method of Example 20, 2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to produce:

[0592] 31a, white solid.

[0593] LC-MS: m / z 691.2[M+H] + .

[0594] 1H-NMR (400MHz, CD3OD) δ7.33 (s, 1H), 7.15-7.03 (m, 3H), 6.67 (d, J = 8.0Hz, 1H ),5.80-5.76(m,1H),5.62-5.58(m,1H),4.26-4.23(m,2H),4.06-4.02(m,2H) ,3.81-3.74(m,1H),3.50-3.44(m,1H),3.29-3.15(m,3H),3.11-3.05(m,2H), 2.91-2.85(m,4H),2.18-1.86(m,11H),1.53-1.46(m,1H),0.99-0.97(m,6H).

[0595] 31b, white solid.

[0596] LC-MS: m / z 691.2[M+H] + .

[0597] 1 H-NMR (400MHz, CD3OD) δ7.43 (s, 1H), 7.16-7.07 (m, 3H), 6.66 (d, J = 8.0Hz, 1H), 5.75 (t, J = 7.6 Hz,1H),5.58-5.54(m,1H),4.33-4.26(m,2H),4.11-4.03(m,2H),3.78-3.72(m,1H),3.56-3. 50(m,1H),3.29-3.26(m,2H),3.20-3.15(m,1H),3.01-2.96(m,5H),2.86-2.83(m,2H),2.20- 2.18(m,2H),1.99(d,J=5.2Hz,6H),1.87-1.82(m,2H),1.40-1.37(m,1H),0.91-0.87(m,6H).

[0598] Example 32: Preparation of (S)-3-((R)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (32a and 32b)

[0599] Referring to the synthetic method of Example 1, 2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was used instead of 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0600] 32a, white solid.

[0601] LC-MS: m / z 684.2[M+H] + .

[0602] 1 H-NMR (400MHz, CD3OD) δ7.82 (s, 1H), 7.11-7.02 (m, 3H), 6.79 (s, 1H), 6.67 (d, J = 2.4H z,1H),6.62(d,J=2.4Hz,1H),5.65-5.60(m,2H),4.34-4.21(m,3H),4.16-3.99(m,5H) ,3.35-3.32(m,2H),2.85(t,J=6.8Hz,2H),2.70-2.68(m,2H),2.48-2.39(m,2H),2.2 5-2.15(m,2H),2.05-1.93(m,6H),1.89(s,3H),1.50-1.38(m,1H),0.96-0.91(m,6H).

[0603] 32b, white solid.

[0604] LC-MS: m / z 684.2[M+H] + .

[0605] 1H NMR (400MHz, CD3OD) δ7.70 (s, 1H), 7.12-7.04 (m, 3H), 6.91 (s, 1H), 6.71 (d, J = 2.4Hz, 1H), 6.66 ( d,J=2.0Hz,1H),5.71-5.68(m,1H),5.62(t,J=7.6Hz,1H),4.39-4.22(m,3H),4.21-4.12(m,5H) ,3.49-3.34(m,2H),2.95-2.90(m,1H),2.86-2.78(m,1H),2.63-2.58(m,1H),2.53-2.45(m,3H) ,2.29-2.17(m,2H),2.04-1.93(m,7H),1.75-1.67(m,1H),1.45-1.37(m,1H),0.90-0.87(m,6H).

[0606] Example 33: Preparation of (S)-3-((R)-2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (33a and 33b)

[0607] Step 1: Preparation of 4-bromo-5-chloropyridin-2-ol (33-1).

[0608] At 0°C, 4-bromo-5-chloropyridin-2-amine (10.00 g, 48.19 mmol) and water (100.0 mL) were added to a beaker, and concentrated sulfuric acid (18.5 mL) was slowly added. The mixture was stirred at room temperature for 15 minutes, and then a solution of sodium nitrite (4.00 g, 57.97 mmol) in water (10.0 mL) was added dropwise. The mixture was reacted at 0°C for 2 hours, and extracted with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10.53 g of a pale yellow liquid crude product, which was used directly in the next reaction.

[0609] LC-MS: m / z 207.8, 209.8 [M+H] + .

[0610] Step 2: Preparation of methyl 2-(4-bromo-5-chloro-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (33-2).

[0611] The crude product of 4-bromo-5-chloropyridin-2-ol (10.53 g), methyl 2-bromo-4-methylpentanoate (11.10 g, 53.11 mmol), and potassium carbonate (13.40 g, 97.10 mmol) were added to N,N-dimethylformamide (100.0 mL) at room temperature and reacted at 80°C for 4 hours. The reaction was quenched with water (300 mL) and extracted with ethyl acetate (200 mL x 3). The filtrate was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-30%) to obtain 6.87 g of the title compound as a light yellow oil, with a two-step yield of 42.4%.

[0612] LC-MS: m / z 336.2, 338.2 [M+H] + .

[0613] Step 3: Preparation of methyl 2-(5-chloro-4-cyclopropyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (33-3).

[0614] At room temperature, under nitrogen atmosphere, methyl 2-(4-bromo-5-chloro-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (6.72 g, 20.00 mmol), cyclopropylboronic acid (1.72 g, 20.00 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (1.46 g, 2.0 mmol), and potassium carbonate (5.55 g, 40.22 mmol) were added to a mixed solvent of dioxane (60.0 mL) and water (12.0 mL). The mixture was reacted at 100°C for 1 hour, and the reaction was quenched with water (150 mL). Ethyl acetate (200 mL x 40) was added. 3) Extraction, the filtrate was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0%-50%) to obtain 3.94 g of the title compound as a yellow liquid, with a yield of 66.1%.

[0615] LC-MS: m / z 298.0 [M+H] + .

[0616] Referring to the synthesis method of Example 7, 2-(5-chloro-4-cyclopropyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid methyl ester was used to replace 2-(3-chloro-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoic acid methyl ester to prepare 2-(4-cyclopropyl-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid.

[0617] LC-MS: m / z 321.2[M+H] + .

[0618] Referring to the synthesis method of Example 20, 2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to produce:

[0619] 33a, white solid.

[0620] LC-MS: m / z 661.9 [M+H] + .

[0621] 1 H-NMR (400MHz, CD3OD) δ7.62 (s, 1H), 7.14-7.02 (m, 3H), 6.60 (d, J = 8.0Hz, 1H), 6.01 (s, 1H ),5.68(t,J=8.0Hz,1H),5.55(t,J=7.2Hz,1H),4.25-4.22(m,2H),4.03-3.99(m,2H),3.39 -3.34(m,2H),3.16-2.96(m,8H),2.83-2.81(m,2H),2.17-2.12(m,2H),2.03-1.86(m,6H) ,1.79(s,3H),1.47-1.40(m,1H),1.17-1.12(m,2H),0.97-0.93(m,6H),0.82-0.77(m,2H).

[0622] 33b, white solid.

[0623] LC-MS: m / z 661.9 [M+H] + .

[0624] 1H-NMR (400MHz, CD3OD) δ7.64 (s, 1H), 7.16-7.06 (m, 3H), 6.66 (d, J = 7.6Hz, 1H), 6.12 (s, 1 H),5.69(t,J=8.0Hz,1H),5.57-5.51(m,1H),4.31-4.25(m,2H),4.10-4.05(m,2H),3.44- 3.34(m,2H),3.18-2.97(m,8H),2.84-2.81(m,2H),2.21-2.16(m,2H),2.00(s,6H),1.93- 1.85(m,1H),1.80-1.77(m,2H),1.37-1.29(m,1H),1.18-1.10(m,2H),0.92-0.78(m,8H).

[0625] Example 34: Preparation of (S)-3-((R)-2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (34a and 34b)

[0626] Referring to the synthesis method of Example 20, 2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to produce:

[0627] 34a, white solid.

[0628] LC-MS: m / z 672.2[M+H] + .

[0629] 11H-NMR (400 MHz, CD3OD) δ 7.80 (s, 1H), 7.14 - 6.97 (m, 3H), 6.84 (t, J = 54.0 Hz, 1H), 6.63 (s, 1H), 6.59 (d, J = 7.6 Hz, 1H), 5.64 (t, J = 8.0 Hz, 1H), 5.49 (t, J = 6.8 Hz, 1H), 4.28 - 4.20 (m, 2H), 4.06 - 3.97 (m, 2H), 3.27 - 3.20 (m, 2H), 3.01 - 2.97 (m, 2H), 2.84 (s, 6H), 2.72 - 2.70 (m, 2H), 2.17 - 2.12 (m, 2H), 1.99 - 1.94 (m, 5H), 1.83 (s, 3H), 1.47 - 1.40 (m, 1H), 0.96 - 0.92 (m, 6H).

[0630] 34b, white solid.

[0631] LC-MS: m / z 672.2 [M + H] + .

[0632] 1 1H-NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.15 - 7.06 (m, 3H), 6.85 (t, J = 54.0 Hz, 1H), 6.74 (s, 1H), 6.65 (d, J = 7.6 Hz, 1H), 5.66 - 5.59 (m, 2H), 4.27 (t, J = 5.6 Hz, 2H), 4.06 (t, J = 5.6 Hz, 2H), 3.30 - 3.23 (m, 2H), 3.07 - 2.98 (m, 2H), 2.89 (s, 6H), 2.71 - 2.58 (m, 2H), 2.23 - 2.15 (m, 2H), 2.00 (s, 6H), 1.95 - 1.88 (m, 1H), 1.79 - 1.72 (m, 1H), 1.42 - 1.35 (m, 1H), 0.89 - 0.87 (m, 6H).

[0633] Example 35: Preparation of (S)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((R)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (35a and 35b)

[0634] With reference to the synthetic method of Example 20, (2,6-dimethylphenyl)boric acid was replaced with (mesitylene)boric acid, and 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was replaced with 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0635] 35a, white solid.

[0636] LC-MS: m / z 734.3[M+H] + .

[0637] 1 H-NMR (400MHz, CD3OD) δ7.85(s,1H),6.88(s,1H),6.84(s,1H),6.72(s,1H),6.58(d,J=8 .0Hz,1H),5.70-5.66(m,1H),5.55-5.52(m,1H),5.38-5.19(m,1H),4.28-4.14(m,4H),4 .04-3.96(m,2H),3.91-3.81(m,2H),3.13-3.09(m,2H),2.82-2.73(m,4H),2.30(s,3H), 2.16-2.13(m,2H),2.00-1.93(m,5H),1.74(s,3H),1.50-1.43(m,1H),0.99-0.94(m,6H).

[0638] 35b, white solid.

[0639] LC-MS: m / z 734.3[M+H] + .

[0640] 1 H-NMR (400MHz, CD3OD) δ7.78 (s, 1H), 6.90-6.88 (m, 3H), 6.65 (d, J = 7.6Hz, 2H), 5 .66-5.61(m,2H),5.41-5.24(m,1H),4.39-4.26(m,4H),4.07-3.92(m,4H),3.30 -3.26(m,2H),2.89-2.78(m,2H),2.71-2.59(m,2H),2.31(s,3H),2.20-2.15(m, 2H),1.96-1.90(m,6H),1.77-1.70(m,1H),1.43-1.32(m,1H),0.91-089(m,6H).

[0641] Example 36: Preparation of (S)-3-((R)-2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (36a and 36b)

[0642] With reference to the synthesis method of Example 20, (2,6-dimethylphenyl)boric acid was substituted with (4-fluoro-2,6-dimethylphenyl)boric acid, and 2-(3-(2-(dimethylamino)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoic acid was substituted with 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0643] 36a, white solid.

[0644] LC-MS: m / z 709.3[M+H] + .

[0645] 1H-NMR (400MHz, CD3OD) δ7.37 (s, 1H), 6.83-6.80 (m, 2H), 6.62 (d, J = 8.0Hz, 1H) ,5.71-5.67(m,1H),5.49(d,J=6.8Hz,1H),4.24(t,J=5.6Hz,2H),4.04(t,J=5. 6Hz,2H),3.70-3.63(m,1H),3.28-3.24(m,2H),2.86(s,6H),2.66-2.63(m,2H ),2.23-1.99(m,7H),1.93-1.84(m,4H),1.47-1.42(m,1H),0.96-0.93(m,6H).

[0646] 36b, white solid.

[0647] LC-MS: m / z 709.3[M+H] + .

[0648] 1 H-NMR (400MHz, CD3OD) δ7.36 (s, 1H), 6.84-6.81 (m, 2H), 6.57 (d, J = 7.6Hz, 1H), 5. 68-5.64(m,1H),5.57-5.53(m,1H),5.35-5.38(m,1H),4.26(t,J=4.8Hz,2H),4.0 7-4.04(m,2H),3.72-3.65(m,1H),3.27-3.23(m,2H),2.93(s,6H),2.63-2.54(m, 2H),2.23-2.16(m,2H),2.06-1.82(m,8H),1.42-1.37(m,1H),0.92-0.89(m,6H).

[0649] Example 37: (S)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((R)-2-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of 3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)propanoic acid (37a and 37b)

[0650] Referring to the synthetic method of Example 20, 2-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0651] 37a, white solid.

[0652] LC-MS: m / z 721.2[M+H] + .

[0653] 1 H-NMR (400MHz, CD3OD) δ7.28 (s, 1H), 7.16-7.06 (m, 3H), 6.62 (d, J = 7.6Hz, 1H), 5 .62-5.58(m,1H),5.50-5.48(m,1H),4.29-4.23(m,2H),4.12-4.01(m,4H),3.82 -3.66(m,3H),3.27-3.16(m,2H),2.98-2.95(m,2H),2.74-2.64(m,2H),2.21-2. 13(m,3H),1.99(s,3H),1.92-1.84(m,4H),1.48-1.42(m,1H),0.95-0.92(m,6H).

[0654] 37b, white solid.

[0655] LC-MS: m / z 721.2[M+H] + .

[0656] 1 H-NMR (400MHz, CD3OD) δ7.36 (s, 1H), 7.16-7.07 (m, 3H), 6.61 (d, J = 8.0Hz, 1H), 5.68-5. 65(m,1H),5.62-5.58(m,1H),5.46-5.31(m,1H),4.54-4.44(m,2H),4.29-4.16(m,4H), 4.07-4.04(m,2H),3.70-3.65(m,1H),3.51-3.48(m,1H),3.11(t,J=6.0Hz,2H),2.67-2 .64(m,2H),2.19-2.16(m,2H),1.99-1.89(m,8H),1.43-1.36(m,1H),0.91-0.88(m,6H).

[0657] Example 38: (S)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((R)-2-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of 3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanamido)propanoic acid (38a and 38b)

[0658] With reference to the synthetic method of Example 20, 2-(3-(2-(3-fluoroazetidin-1-yl)ethyl)-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (4-fluoro-2,6-dimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0659] 38a, white solid.

[0660] LC-MS: m / z 739.3[M+H] + .

[0661] 1 H-NMR (400MHz, CD3OD) δ7.29 (s, 1H), 6.84-6.81 (m, 2H), 6.64 (d, J = 8.0Hz, 1H), 5.64-5 .60(m,1H),5.51(t,J=6.8Hz,1H),5.41-5.22(m,1H),4.30-3.79(m,8H),3.46-3.39(m ,1H),3.30-3.27(m,1H),3.05-2.98(m,2H),2.08-2.03(m,1H),2.76-2.71(m,2H),2.2 3-2.13(m,3H),1.99(s,3H),1.92-1.83(m,4H),1.48-1.41(m,1H),0.95-0.92(m,6H).

[0662] 38b, white solid.

[0663] LC-MS: m / z 739.3[M+H] + .

[0664] 1 H-NMR (400MHz, CD3OD) δ7.36 (s, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.59 (d, J = 8.0H z,1H),5.67-5.67(m,2H),5.47-5.29(m,1H),4.53-4.42(m,2H),4.29-4.05(m,6 H),3.70-3.64(m,1H),3.51-3.45(m,1H),3.10(t,J=6.0Hz,2H),2.65-2.60(m,2 H),2.21-2.15(m,2H),2.00-1.88(m,9H),1.44-1.37(m,1H),0.92-0.89(m,6H).

[0665] Example 39: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (39a and 39b)

[0666] With reference to the synthetic method of Example 20, 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (4-fluoro-2,6-dimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0667] 39a, white solid.

[0668] LC-MS: m / z 694.2[M+H] + .

[0669] 1H-NMR (400MHz, CD3OD) δ9.18 (d, J=7.6Hz, 1H), 7.92 (s, 1H), 6.84-6.74 (m, 3H ),6.62(d,J=8.0Hz,1H),5.62-5.52(m,2H),4.26-4.22(m,2H),4.04-4.01(m, 2H),3.31-3.23(m,2H),3.09-2.94(m,8H),2.88-2.82(m,2H),2.19-2.12(m,3 H), 2.01-1.94 (m, 4H), 1.78 (s, 3H), 1.40-1.34 (m, 2H), 1.00 (t, J = 7.2Hz, 3H).

[0670] 39b, white solid.

[0671] LC-MS: m / z 694.2[M+H] + .

[0672] 1 H-NMR(400MHz,CD3OD)δ9.14(d,J=8.0Hz,1H),7.95(s,1H),6.90-6.83(m,3H),6.68(d,J =7.6Hz,1H),5.65-5.61(m,1H),5.56-5.53(m,1H),4.31-4.27(m,2H),4.11-4.06(m,2H) ,3.40-3.34(m,2H),3.28-3.20(m,1H),3.09-2.95(m,7H),2.88-2.81(m,2H),2.23-2.16 (m,2H),2.05-1.96(m,7H),1.92-1.82(m,1H),1.28-1.19(m,2H),0.91(t,J=7.2Hz,3H).

[0673] Example 40: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (40a and 40b)

[0674] With reference to the synthetic method of Example 20, 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (mesitylenetrimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0675] 40a, white solid.

[0676] LC-MS: m / z 690.2[M+H] + .

[0677] 1 H-NMR (400MHz, CD3OD) δ9.17 (d, J = 7.6Hz, 1H), 7.95 (s, 1H), 6.90-6.89 (m, 3H), 6. 67(d,J=8.0Hz,1H),5.65-5.53(m,2H),4.28-4.26(m,2H),4.07-4.04(m,2H),3.39 -3.35(m,1H),3.20-3.15(m,1H),3.09-2.99(m,8H),2.85-2.82(m,2H),2.30(s,3H ),2.21-2.15(m,2H),2.06-1.82(m,8H),1.30-1.16(m,2H),0.90(t,J=7.6Hz,3H).

[0678] 40b, white solid.

[0679] LC-MS: m / z 690.2[M+H] + .

[0680] 1 H-NMR (400MHz, CD3OD) δ9.19 (d, J=7.6Hz, 1H), 7.92 (s, 1H), 6.92-6.83 (m, 2H), 6.72 (s,1H),6.60(d,J=8.0Hz,1H),5.63-5.52(m,2H),4.32-4.18(m,2H),4.11-3.96(m, 2H),3.30-3.24(m,2H),3.04-2.96(m,8H),2.87-2.80(m,2H),2.30(s,3H),2.21-2. 10(m,3H),2.00-1.91(m,4H),1.71(s,3H),1.41-1.32(m,2H),1.00(t,J=7.6Hz,3H).

[0681] Example 41: Preparation of (S)-3-((R)-2-(3-(2-(dimethylamino)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(3-(2-(dimethylamino)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (41a and 41b)

[0682] Referring to the synthesis method of Example 1, 2-(3-(2-(dimethylamino)ethyl)-5-methyl-6-oxopyridazin-1(6H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0683] 41a, white solid.

[0684] LC-MS: m / z 619.4 [M+H] + .

[0685] 1 H-NMR(400MHz,CD3OD)δ7.38(d,J=1.2Hz,1H),7.14-7.04(m,3H),6.64(d,J=2.0Hz,1H),6.5 8(d,J=2.0Hz,1H),5.64-5.60(m,1H),5.42(t,J=4.8Hz,1H),4.36-4.23(m,3H),4.16-4.10(m ,1H),3.48-3.28(m,2H),3.06-2.99(m,1H),2.91-2.86(m,1H),2.57-2.45(m,8H),2.24-2.1 5(m,6H),2.02(s,3H),1.98(s,3H),1.85-1.78(m,1H),1.38-1.33(m,1H),0.89-0.87(m,6H).

[0686] 41b, white solid.

[0687] LC-MS: m / z 619.4 [M+H] + .

[0688] 1H-NMR (400MHz, CD3OD) δ7.21 (s, 1H), 7.12-7.03 (m, 3H), 6.61 (d, J = 2.0Hz, 1H) ,6.49(d,J=2.0Hz,1H),5.65-5.61(m,1H),5.52-5.49(m,1H),4.31-4.11(m,4 H),3.57-3.39(m,2H),3.03(t,J=6.4Hz,2H),2.86(s,6H),2.63-2.51(m,2H), 2.26-2.16(m,2H),2.08-1.80(m,11H),1.42-1.35(m,1H),0.88-0.87(m,6H).

[0689] Example 42: (S)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((R)-2-(5-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of 3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(5-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (42a and 42b)

[0690] Referring to the synthesis method of Example 20, 2-(5-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to produce:

[0691] 42a, white solid.

[0692] LC-MS: m / z 734.7[M+H] + .

[0693] 11H-NMR (400 MHz, CD3OD) δ 9.20 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.14 - 7.00 (m, 3H), 6.75 (s, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.73 (t, J = 8.0 Hz, 1H), 5.57 - 5.44 (m, 2H), 4.26 - 4.22 (m, 2H), 4.04 - 4.00 (m, 2H), 3.90 (br, 2H), 3.46 - 3.42 (m, 2H), 3.08 - 3.00 (m, 2H), 2.84 - 2.82 (m, 2H), 2.51 - 2.42 (m, 2H), 2.19 - 2.12 (m, 2H), 2.00 - 1.95 (m, 5H), 1.77 (s, 3H), 1.52 - 1.44 (m, 1H), 1.32 (d, J = 4.0 Hz, 2H), 1.00 - 0.96 (m, 6H).

[0694] 42b, white solid.

[0695] LC-MS: m / z 734.7 [M+H] + .

[0696] 1H NMR (400 MHz, CD3OD) δ 7.86 (s, 1H), 7.12 - 7.04 (m, 3H), 6.84 (s, 1H), 6.62 (d, J = 7.6 Hz, 1H), 5.63 - 5.54 (m, 2H), 5.36 - 5.23 (m, 1H), 4.25 (t, J = 5.6 Hz, 2H), 4.03 (t, J = 6.4 Hz, 2H), 3.36 - 3.35 (m, 1H), 3.20 - 3.11 (m, 3H), 2.92 - 2.88 (m, 2H), 2.64 - 2.58 (m, 2H), 2.36 - 2.12 (m, 5H), 2.04 - 1.88 (m, 8H), 1.74 - 1.67 (m, 1H), 1.41 - 1.32 (m, 1H), 0.88 - 0.86 (m, 6H).

[0697] Example 43: (S)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((R)-2-(5-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of 3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(5-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (43a and 43b)

[0698] With reference to the synthetic method of Example 20, 2-(5-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (4-fluoro-2,6-dimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0699] 43a, white solid.

[0700] LC-MS: m / z 752.7[M+H] + .

[0701] 1 H-NMR(400MHz,CD3OD)δ9.19(d,J=7.6Hz,1H),7.91(s,1H),6.81-6.74(m,3H),6.60- 6.58(m,1H),5.71(t,J=8.0Hz,1H),5.55-5.42(m,2H),4.26-4.18(m,2H),4.04-3.95 (m,2H),3.67(s,2H),3.44-3.40(m,2H),3.06-2.96(m,2H),2.82-2.80(m,2H),2.68( s,1H),2.42(br,2H),2.16-2.11(m,2H),1.97-1.92(m,5H),1.76(s,3H),1.49-1.42(m 1H),1.32-1.30(m,1H),0.98-0.93(m,6H).

[0702] 43b, white solid.

[0703] LC-MS: m / z 752.7[M+H] + .

[0704] 1 H-NMR(400MHz,CD3OD)δ9.21(d,J=8.0Hz,1H),7.97(s,1H),6.90(s,1H),6.84(d,J=9.6Hz,2H), 6.66(d,J=8.0Hz,1H),5.75(t,J=8.0Hz,1H),5.56-5.44(m,2H),4.30-4.27(m,2H),4.09-4.06(m ,2H),3.90(br,2H),3.50-3.46(m,2H),3.07-3.02(m,2H),2.85-2.68(m,3H),2.48-2.44(m,2H), 2.20-2.16(m,2H),2.01(s,6H),1.83(t,J=7.6Hz,2H),1.39-1.32(m,2H),0.90(t,J=6.0Hz,6H).

[0705] Example 44: Preparation of (S)-3-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((R)-2-(5-(2-(S)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S)-3-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(5-(2-(S)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (44a and 44b)

[0706] With reference to the synthetic method of Example 20, 2-(5-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (mesitylenetrimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0707] 44a, white solid.

[0708] LC-MS: m / z 748.8[M+H] + .

[0709] 1 1H-NMR (400 MHz, CD3OD) δ 8.29 (br, 1H), 7.88 (s, 1H), 6.85 (s, 1H), 6.81 (s, 1H), 6.69 (s, 1H), 6.55 (d, J = 8.0 Hz, 1H), 5.68 - 5.64 (m, 1H), 5.51 - 5.48 (m, 1H), 5.40 - 5.24 (m, 1H), 4.25 - 4.15 (m, 2H), 4.03 - 3.94 (m, 2H), 3.49 - 3.36 (m, 2H), 3.26 - 3.12 (m, 2H), 3.09 - 2.99 (m, 2H), 2.94 - 2.85 (m, 2H), 2.77 - 2.74 (m, 2H), 2.41 - 2.24 (m, 5H), 2.13 - 2.10 (m, 2H), 1.99 - 1.85 (m 5H), 1.70 (s, 3H), 1.49 - 1.39 (m, 1H), 0.96 - 0.91 (m, 6H).

[0710] 44b, white solid.

[0711] LC-MS: m / z 748.8 [M+H] + . <00's 1928>

[0712] 1H-NMR (400 MHz, CD3OD) δ 8.36 (br, 1H), 7.89 (s, 1H), 6.90 - 6.88 (m, 3H), 6.63 (d, J = 8.0 Hz, 1H), 5.66 - 5.57 (m, 2H), 5.42 - 5.28 (m, 1H), 4.26 (t, J = 5.2 Hz, 2H), 4.05 (t, J = 5.2 Hz, 2H), 3.51 - 3.37 (m, 4H), 3.29 - 3.18 (m, 2H), 2.97 - 2.94 (m, 2H), 2.72 - 2.59 (m, 2H), 2.42 - 2.28 (s, 5H), 2.20 - 2.14 (m, 2H), 2.00 - 1.90 (m, 7H), 1.77 - 1.70 (m, 1H), 1.43 - 1.32 (m, 1H), 0.92 - 0.88 (m, + 6H).

[0713] It should be noted that there seems to be an error in the original text where "00's 1928" in line is likely incorrect. It should probably be something like " ". Also, the "+ 6H" in line seems incorrect and should be adjusted according to the correct chemical structure or data.Example 45: (S)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((R)-2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of 3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (45a and 45b)

[0714] Referring to the synthesis method of Example 20, 2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to produce:

[0715] 45a, white solid.

[0716] LC-MS: m / z 734.7[M+H] + .

[0717] 1 H-NMR(400MHz,CD3OD)δ8.45(br,1H),7.92(s,1H),7.13-7.00(m,3H),6.71(s,1H),6.5 9(d,J=8.0Hz,1H),5.69-5.65(m,1H),5.54-5.50(m,1H),5.36-5.20(m,2H),4.29-4.18 (m,2H),4.06-3.95(m,2H),3.26-3.15(m,2H),3.08-2.70(m,6H),2.38-2.03(m,5H),2. 02-1.89(m,4H),1.77(s,3H),1.64-1.59(m,1H),1.49-1.42(m,1H),0.98-0.93(m,6H).

[0718] 45b, white solid.

[0719] LC-MS: m / z 734.7[M+H] + .

[0720] 1H-NMR(400MHz,CD3OD)δ8.44(br,1H),7.86(s,1H),7.15-7.06(m,3H),6.88(s,1H),6.65(d ,J=7.6Hz,1H),5.65-5.57(m,2H),5.43-5.27(m,1H),4.27(t,J=5.6Hz,2H),4.06(t,J=5.6H z,2H),3.52-3.38(m,2H),3.29-3.15(m,4H),2.96-2.90(m,2H),2.70-2.57(m,2H),2.40-2 .15(m,4H),2.00-1.90(m,7H),1.77-1.70(m,1H),1.44-1.34(m,1H),0.89(d,J=6.8Hz,6H).

[0721] Example 46: (S)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((R)-2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S Preparation of 3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (46a and 46b)

[0722] With reference to the synthetic method of Example 20, 2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (4-fluoro-2,6-dimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0723] 46a, white solid.

[0724] LC-MS: m / z 752.7[M+H] + .

[0725] 1H-NMR (400MHz, CD3OD) δ7.92 (s, 1H), 6.83-6.72 (m, 3H), 6.59 (d, J = 8.0Hz, 1H), 5. 69-5.65(m,1H),5.51(t,J=7.2Hz,1H),5.36-5.21(m,1H),4.29-4.18(m,2H),4.0 7-3.96(m,2H),3.28-3.21(m,2H),3.12-2.86(m,6H),2.78-2.76(m,2H),2.37-2. 14(m,4H),2.00-1.92(m,5H),1.78(s,3H),1.50-1.41(m,1H),0.98-0.93(m,6H).

[0726] 46b, white solid.

[0727] LC-MS: m / z 752.7[M+H] + .

[0728] 1 H-NMR(400MHz,CD3OD)δ8.43(br,1H),7.86(s,1H),6.88-6.82(m,3H),6.65(d,J=7.6Hz ,1H),5.65-5.56(m,2H),5.43-5.28(m,1H),4.27(t,J=5.6Hz,2H),4.06(t,J=5.6Hz,2H ),3.50-3.40(m,2H),3.30-3.14(m,4H),2.96-2.94(m,2H),2.71-2.58(m,2H),2.41-2. 15(m,4H),2.00-1.90(m,7H),1.78-1.71(m,1H),1.44-1.34(m,1H),0.91-0.88(m,6H).

[0729] Example 47: Preparation of (S)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((R)-2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid and (S)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)-3-((S)-2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid (47a and 47b)

[0730] Referring to the synthetic method of Example 20, 2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (mesitylenetrimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0731] 47a, white solid.

[0732] LC-MS: m / z 748.8[M+H] + .

[0733] 1 H-NMR(400MHz,CD3OD)δ8.29(s,1H),7.90(s,1H),6.85(s,1H),6.81(s,1H),6.69(s,1H),6.55(d, J=8.0Hz,1H),5.68-5.64(m,1H),5.51-5.47(m,1H),5.38-5.23(m,1H),4.25-4.15(m,2H),4.03-3 .92(m,2H),3.43-3.34(m,2H),3.23-3.00(m,4H),2.94-2.86(m,2H),2.79-2.72(m,2H),2.38-2.1 7(m,5H),2.13-2.10(m,2H),1.99-1.86(m,5H),1.70(s,3H),1.48-1.41(m,1H),0.96-0.91(m,6H).

[0734] 47b, white solid.

[0735] LC-MS: m / z 748.8[M+H] + .

[0736] 1H NMR (400MHz, CD3OD) δ7.86 (s, 1H), 6.90-6.88 (m, 3H), 6.63 (d, J = 8.0Hz, 1H), 5.65-5.57 ( m,2H),5.44-5.28(m,1H),4.26(t,J=5.6Hz,2H),4.05(t,J=5.6Hz,2H),3.54-3.41(m,2H ),3.29-3.15(m,4H),2.96-2.64(m,2H),2.70-2.58(m,2H),2.41-2.25(m,5H),2.20-2.0 0(m,2H),2.00-1.90(m,7H),1.79-1.70(m,1H),1.43-1.37(m,1H),0.89(d,J=6.4Hz,6H).

[0737] Example 48: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (48a and 48b)

[0738] Referring to the synthesis method of Example 20, (4-fluoro-2,6-dimethylphenyl)boric acid was used instead of (2,6-dimethylphenyl)boric acid to prepare:

[0739] 48a, white solid.

[0740] LC-MS: m / z 708.1[M+H] + .

[0741] 1H-NMR (400MHz, CD3OD) δ9.21 (d, J = 7.6Hz, 1H), 7.93 (s, 1H), 6.84-6.76 (m, 3H), 6. 61(d,J=8.0Hz,1H),5.72(t,J=8.0Hz,1H),5.57-5.51(m,1H),4.29-4.19(m,2H),4 .07-3.98(m,2H),3.30-3.27(m,2H),3.08-2.94(m,8H),2.89-2.78(m,2H),2.21-2 .13(m,2H),2.04-1.94(m,5H),1.78(s,3H),1.51-1.45(m,1H),1.00-0.94(m,6H).

[0742] 48b, white solid.

[0743] LC-MS: m / z 708.1[M+H] + .

[0744] 1 H-NMR (400MHz, CD3OD) δ9.21 (d, J = 8.0Hz, 1H), 7.96 (s, 1H), 6.90-6.83 (m, 3H), 6.66 ( d,J=7.6Hz,1H),5.75(t,J=8.0Hz,1H),5.56-5.52(m,1H),4.30-4.26(m,2H),4.09-4. 06(m,2H),3.32-3.29(m,2H),3.05-2.96(m,8H),2.85-2.83(m,2H),2.22-2.16(m,2H ), 2.06-2.01 (s, 6H), 1.83 (t, J = 7.6Hz, 2H), 1.38-1.33 (m, 1H), 0.90 (t, J = 6.4Hz, 6H).

[0745] Example 49: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (49a and 49b)

[0746] Referring to the synthesis method of Example 20, (trimethylphenyl)boric acid was used instead of (2,6-dimethylphenyl)boric acid to prepare:

[0747] 49a, white solid.

[0748] LC-MS: m / z 704.1[M+H] + .

[0749] 1 H-NMR(400MHz,CD3OD)δ9.21(d,J=8.0Hz,1H),7.93(s,1H),6.88(s,1H),6.83(s,1H),6.7 4(s,1H),6.59(d,J=8.0Hz,1H),5.75-5.70(m,1H),5.57-5.51(m,1H),4.26-4.21(m,2H), 4.04-3.99(m,2H),3.31-3.27(m,2H),3.08-2.98(m,8H),2.87-2.81(m,2H),2.30(s,3H), 2.21-2.11(m,2H),2.00-1.93(m,5H),1.71(s,3H),1.51-1.45(m,1H),1.00-0.95(m,6H).

[0750] 49b, white solid.

[0751] LC-MS: m / z 704.1[M+H] + .

[0752] 1 H-NMR (400MHz, CD3OD) δ7.94 (s, 1H), 6.91-6.90 (m, 3H), 6.65 (d, J = 8.0Hz, 1H), 5.74-5. 70(m,1H),5.56(t,J=7.2Hz,1H),4.27(t,J=5.2Hz,2H),4.06(t,J=5.2Hz,2H),3.32-3.2 7(m,2H),3.05-2.97(m,7H),2.80-2.78(m,2H),2.31(s,3H),2.23-2.15(m,2H),2.06-1 .94(m,6H),1.88-1.80(m,2H),1.66-1.60(m,1H),1.37-1.32(m,1H),0.90-0.88(m,6H).

[0753] Example 50: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (50a and 50b)

[0754] Referring to the synthesis method of Example 20, 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to produce:

[0755] 50a, white solid.

[0756] LC-MS: m / z 676.5[M+H] + .

[0757] 1 H-NMR(400MHz,CD3OD)δ9.16(d,J=7.6Hz,1H),7.92(s,1H),7.14-7.00(m,3H),6 .73(s,1H),6.62(d,J=8.0Hz,1H),5.63-5.53(m,2H),4.26-4.22(m,2H),4.04-4. 00(m,2H),3.31-3.28(m,2H),3.04-2.94(m,8H),2.88-2.80(m,2H),2.18-2.11( m,3H),2.02-1.93(m,4H),1.77(s,3H),1.40-1.34(m,2H),0.99(t,J=7.2Hz,3H).

[0758] 50b, white solid.

[0759] LC-MS: m / z 676.5[M+H] + .

[0760] 1H-NMR (400MHz, CD3OD) δ9.14 (d, J = 8.0Hz, 1H), 7.95 (s, 1H), 7.16-7.07 (m, 3H), 6. 89(s,1H),6.68(d,J=8.0Hz,1H),5.65-5.54(m,2H),4.29-4.27(m,2H),4.08-4.06 (m,2H),3.38-3.34(m,2H),3.05-2.96(m,8H),2.85-2.83(m,2H),2.23-2.16(m,2H ),2.06-1.97(m,7H),1.91-1.82(m,1H),1.28-1.19(m,2H),0.90(t,J=7.2Hz,3H).

[0761] Example 51: Preparation of (S)-3-((R)-2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (51a and 51b)

[0762] With reference to the synthesis method of Example 20, 2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (mesitylenetrimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0763] 51a, white solid.

[0764] LC-MS: m / z 686.4[M+H] + .

[0765] 1H-NMR(400MHz,CD3OD)δ8.46(br,1H),7.80(s,1H),6.98-6.71(m,3H),6.64(s,1H),6.56(d ,J=8.0Hz,1H),5.65(t,J=8.0Hz,1H),5.48(t,J=6.8Hz,1H),4.26-4.21(m,2H),4.06-3.96 (m,2H),3.27-3.20(m,2H),3.01-2.98(m,2H),2.85(s,6H),2.72-2.70(m,2H),2.30(s,3H) ,2.17-2.13(m,2H),1.98-1.94(s,5H),1.79(s,3H),1.47-1.38(m,1H),0.97-0.92(m,6H).

[0766] 51b, white solid.

[0767] LC-MS: m / z 686.4[M+H] + .

[0768] 1 H-NMR (400MHz, CD3OD) δ7.85 (s, 1H), 7.00-6.73 (m, 4H), 6.65 (d, J = 7.6Hz, 1H), 5 .76-5.72(m,1H),5.55(t,J=7.6Hz,1H),4.27(t,J=6.0Hz,2H),4.06(t,J=5.6Hz ,2H),2.28-2.25(m,2H),3.05-2.97(m,7H),2.81-2.77(m,2H),2.31(s,3H),2.2 3-2.12(m,2H),1.96(s,6H),1.84-1.80(m,2H),1.34(m,2H),0.90-0.87(m,6H).

[0769] Example 52: Preparation of (S)-3-((R)-3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propionamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propionamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (52a and 52b)

[0770] Referring to the synthesis method of Example 20, 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propanoic acid was replaced with 3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propanoic acid to produce:

[0771] 52a, white solid.

[0772] LC-MS: m / z 688.2[M+H] + .

[0773] 1 H-NMR (400MHz, CD3OD) δ9.19 (d, J = 7.6Hz, 1H), 7.93 (s, 1H), 7.14-7.00 (m, 3H), 6.73 (s, 1H), 6. 63(d,J=8.0Hz,1H),5.68(t,J=8.0Hz,1H),5.58-5.53(m,1H),4.30-4.21(m,2H),4.06-3.98(m, 2H),3.30-3.28(m,2H),3.04-2.96(m,8H),2.85-2.83(m,2H),2.18-2.12(m,2H),2.05-1.89(m ,5H),1.76(s,3H),0.73-0.67(m,1H),0.53-0.49(m,2H),0.24-0.20(m,1H),0.14-0.10(m,1H).

[0774] 52b, white solid.

[0775] LC-MS: m / z 688.2[M+H] + .

[0776] 1H-NMR(400MHz,CD3OD)δ9.17(d,J=8.0Hz,1H),7.97(s,1H),7.16-7.06(m,3H),6.90(s,1H),6.68( d,J=7.6Hz,1H),5.69(t,J=7.6Hz,1H),5.59-5.53(m,1H),4.29-4.26(m,2H),4.10-4.03(m,2H),3 .38-3.34(m,2H),3.04-2.96(m,8H),2.87-2.81(m,2H),2.21-2.16(m,2H),2.00(s,3H),1.97(s,3 H),1.94-1.89(m,1H),1.82-1.74(m,1H),0.59-0.52(m,1H),0.36-0.27(m,2H),0.09-0.03(m,2H).

[0777] Example 53: (S)-3-((R)-3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propionamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S Preparation of 3-((S)-3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propionamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (53a and 53b)

[0778] With reference to the synthetic method of Example 20, 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (4-fluoro-2,6-dimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0779] 53a, white solid.

[0780] LC-MS: m / z 706.5[M+H] + .

[0781] 11H-NMR (400 MHz, CD3OD) δ 9.19 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 6.85 - 6.74 (m, 3H), 6.63 (d, J = 8.0 Hz, 1H), 5.68 (t, J = 8.0 Hz, 1H), 5.56 - 5.53 (m, 1H), 4.26 - 4.22 (m, 2H), 4.04 - 4.01 (m, 2H), 3.30 - 3.28 (m, 2H), 3.04 - 2.96 (m, 8H), 2.85 - 2.82 (m, 2H), 2.23 - 2.13 (m, 2H), 2.05 - 1.90 (m, 5H), 1.77 (s, 3H), 0.74 - 0.68 (m, 1H), 0.52 - 0.48 (m, 2H), 0.23 - 0.20 (m, 1H), 0.15 - 0.12 (m, 1H).

[0782] 53b, white solid.

[0783] LC-MS: m / z 706.5 [M+H] + .

[0784] 1 1H-NMR (400 MHz, CD3OD) δ 9.16 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 6.90 (s, 1H), 6.86 - 6.81 (m, 2H), 6.68 (d, J = 7.6 Hz, 1H), 5.69 (t, J = 8.0 Hz, 1H), 5.57 - 5.53 (m, 1H), 4.30 - 4.24 (m, 2H), 4.09 - 4.04 (m, 2H), 3.36 - 3.34 (m, 2H), 3.04 - 2.98 (m, 8H), 2.87 - 2.83 (m, 2H), 2.21 - 2.16 (m, 2H), 2.00 - 1.88 (m, 7H), 1.83 - 1.76 (m, 1H), 0.58 - 0.52 (m, 1H), 0.37 - 0.28 (m, 2H), 0.09 - 0.00 (m, 2H).

[0785] Example 54: Preparation of (S)-3-((R)-3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propionamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propionamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (54a and 54b)

[0786] Referring to the synthetic method of Example 20, 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)propanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (mesitylene)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0787] 54a, white solid.

[0788] LC-MS: m / z 702.3[M+H] + .

[0789] 1 H-NMR(400MHz,CD3OD)δ9.19(d,J=7.6Hz,1H),7.93(s,1H),6.89(s,1H),6.83(s,1H),6.72(s,1H), 6.61(d,J=8.0Hz,1H),5.68(t,J=8.0Hz,1H),5.56-5.52(m,1H),4.28-4.13(m,2H),4.02-3.99(m,2H ),3.29-3.27(m,2H),3.06-2.93(m,8H),2.88-2.78(m,2H),2.30(s,3H),2.17-2.11(m,2H),2.05-1. 89(m,5H),1.71(s,3H),0.72-0.66(m,1H),0.53-0.50(m,2H),0.24-0.20(m,1H),0.14-0.10(m,1H).

[0790] 54b, white solid.

[0791] LC-MS: m / z 702.3[M+H] + .

[0792] 1 H-NMR (400MHz, CD3OD) δ9.17(d,J=8.0Hz,1H),7.97(s,1H),6.90-6.89(m,3H),6.67(d,J=8 .0Hz,1H),5.69(t,J=8.0Hz,1H),5.57-5.54(m,1H),4.28-4.21(m,2H),4.07-4.04(m,2H),3 .37-3.31(m,2H),3.04-2.97(m,8H),2.86-2.84(m,2H),2.30(s,3H),2.21-2.15(m,2H),1.9 6-1.89(m,7H),1.82-1.74(m,1H),0.58-0.52(m,1H),0.36-0.27(m,2H),0.09-0.00(m,2H).

[0793] Example 55: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (55a and 55b)

[0794] Step 1: Preparation of (S)-3-((R)-2-(5-(2-(dimethylamino)ethyl)-4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoic acid (Compounds 55a and 55b).

[0795] At room temperature under nitrogen atmosphere, ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methoxy-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(8-(2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-6-yl)propanoate (400 mg, 0.60 mmol) was dissolved in N-methylpyrrolidone (5.0 mL). Sodium hydroxide (120 mg, 3.00 mmol) and n-dodecylmercaptan (606 mg, 3.00 mmol) were added, and the mixture was heated to 120°C for 4 hours. 1N hydrochloric acid solution was added dropwise to adjust the pH to 6-7, and the mixture was concentrated under reduced pressure. The residue was separated by high-pressure preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile / water, gradient: 10%-50%, 0.05% formic acid) to obtain a pair of diastereomers:

[0796] 55a, white solid, 64 mg, yield 33.2%.

[0797] LC-MS: m / z 620.3[M+H] + .

[0798] 1 H-NMR (400MHz, DMSO-d6) δ10.99 (s, 1H), 9.40 (s, 1H), 8.68 (d, J = 8.4Hz, 1H), 7.52 (s, 1H), 7. 15-7.04(m,3H),6.72(d,J=2.0Hz,1H),6.60(d,J=2.0Hz,1H),5.60(s,1H),5.57-5.50(m,2H ),4.17-4.03(m,4H),3.15-3.08(m,2H),2.81(d,J=4.4Hz,6H),2.73-2.59(m,4H),2.14-2.0 6(m,2H),1.96(s,3H),1.84(s,3H),1.79-1.66(m,2H),1.35-1.29(m,1H),0.87-0.82(m,6H).

[0799] 55b, white solid, 30 mg, yield 8.0%.

[0800] LC-MS: m / z 620.3[M+H] + .

[0801] 1H-NMR(400MHz,DMSO-d6)δ8.89(d,J=8.0Hz,1H),7.57(s,1H),7.16-7.08(m,3H),6.73 (d,J=2.0Hz,1H),6.63(d,J=2.0Hz,1H),5.67(s,1H),5.59-5.53(m,2H),4.23-4.06(m ,4H),3.14(t,J=7.6Hz,1H),2.81(s,6H),2.73-2.67(m,4H),2.34-2.33(m,1H),2.16- 2.12(m,2H),1.97(s,6H),1.65-1.49(m,2H),1.21-1.15(m,1H),0.73(t,J=6.0Hz,6H).

[0802] Example 56: (S)-3-((R)-2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S Preparation of )-3-((S)-2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (56a and 56b)

[0803] Referring to the synthetic method of Example 20, 2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to obtain:

[0804] 56a, white solid.

[0805] LC-MS: m / z 738.4[M+H] + .

[0806] 1H-NMR(400MHz,CD3OD)δ7.90 - 7.86(s,1H), 7.12 - 6.98(m,3H), 6.73(s,1H), 6.62 - 6.58(m,1H), 5.71(t, J = 8.0Hz,1H), 5.56 - 5.52(m,1H), 4.67(t, J = 11.2Hz,3H), 4.24 - 4.20(m,2H), 4.10 - 3.96(m,3H), 3.86(t, J = 15.2Hz,1H), 3.49 - 3.40(m,2H), 3.02 - 2.98(m,1H), 2.88 - 2.80(m,3H), 2.16 - 2.10(m,2H), 2.03 - 1.93(m,4H), 1.75(s,3H), 1.50 - 1.42(m,1H), 0.98 - 0.93(m,6H).

[0807] 56b, white solid.

[0808] LC-MS: m / z 738.4[M + H] + .

[0809] 1 H-NMR(400MHz,CD3OD)δ7.92 - 7.90(s,1H), 7.14 - 7.05(m,3H), 6.88(s,1H), 6.64(d, J = 7.6Hz,1H), 5.76 - 5.72(m,1H), 5.56 - 5.52(m,1H), 4.70(t, J = 11.2Hz,2H), 4.26(t, J = 5.6Hz,2H), 4.07 - 4.04(m,3H), 3.87(t, J = 15.6Hz,1H), 3.50 - 3.45(m,2H), 3.04 - 2.99(m,1H), 2.91 - 2.81(m,3H), 2.19 - 2.14(m,2H), 1.99(s,6H), 1.83 - 1.79(m,2H), 1.37 - 1.32(m,1H), 0.88 - 0.86(m,6H).

[0810] Example 57: (S)-3-((R)-2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S Preparation of )-3-((S)-2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (57a and 57b)

[0811] With reference to the synthetic method of Example 20, 2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (4-fluoro-2,6-dimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0812] 57a, white solid.

[0813] LC-MS: m / z 756.3[M+H] + .

[0814] 1 H-NMR (400MHz, CD3OD) δ7.9-7.86(m,1H),6.82-6.74(m,3H),6.61-6.58(m,1H),5.73-5. 69(m,1H),5.55-5.52(m,1H),4.64(t,J=11.2Hz,3H),4.26-4.19(m,2H),4.10-3.98(m,3H ),3.86(t,J=15.2Hz,1H),3.43-3.37(m,2H),3.02-2.98(m,1H),2.88-2.80(m,3H),2.19- 2.11(m,2H),1.96-1.74(m,4H),1.78-1.75(m,3H),1.50-1.42(m,1H),0.98-0.94(m,6H).

[0815] 57b, white solid.

[0816] LC-MS: m / z 756.3[M+H]+ .

[0817] 1 H-NMR (400MHz, CD3OD) δ7.91-7.90(m,1H),6.88-6.81(m,3H),6.64(d,J=7.6Hz,1H),5.73(t, J=8.0Hz,1H),5.54-5.50(m,1H),4.56(t,J=11.2Hz,2H),4.26(t,J=5.6Hz,2H),4.10-4.04(m ,3H),3.85(t,J=15.2Hz,1H),3.40-3.36(m,1H),3.03-2.99(m,1H),2.87-2.81(m,3H),2.21- 2.14(m,2H),2.04-1.99(m,7H),1.84-1.77(m,2H),1.37-1.32(m,1H),0.88(t,J=6.4Hz,6H).

[0818] Example 58: Preparation of (S)-3-((R)-2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (58a and 58b)

[0819] With reference to the synthetic method of Example 20, 2-(5-(2-(3,3-difluoroazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (mesitylenetrimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0820] 58a, white solid.

[0821] LC-MS: m / z 752.6[M+H] + .

[0822] 1H-NMR(400MHz, CD3OD) δ 7.91 - 7.86 (m, 1H), 6.87 - 6.82 (m, 2H), 6.72 (d, J = 4.8Hz, 1H), 6.60 - 6.56 (m, 1H), 5.72 (t, J = 8.0Hz, 1H), 5.56 - 5.51 (m, 1H), 4.73 (t, J = 11.2Hz, 2H), 4.26 - 4.18 (m, 2H), 4.10 - 3.97 (m, 3H), 3.86 (t, J = 15.2Hz, 1H), 3.52 - 3.40 (m, 2H), 3.02 - 2.98 (m, 1H), 2.92 - 2.79 (m, 3H), 2.28 (s, 3H), 2.15 - 2.10 (m, 2H), 1.97 - 1.92 (m, 5H), 1.71 - 1.69 (m, 3H), 1.50 - 1.42 (m, 1H), 0.98 - 0.93 (m, 6H).

[0823] 58b, white solid.

[0824] LC-MS: m / z 752.6 [M + H] + .

[0825] 1 H-NMR(400MHz, CD3OD) δ 7.92 - 7.90 (m, 1H), 6.89 - 6.87 (m, 3H), 6.63 (d, J = 7.6Hz, 1H), 5.74 (t, J = 8.0Hz, 1H), 5.55 - 5.50 (m, 1H), 4.64 (t, J = 11.2Hz, 2H), 4.25 (t, J = 5.6Hz, 2H), 4.10 - 4.03 (m, 3H), 3.86 (t, J = 15.2Hz, 1H), 3.46 - 3.41 (m, 2H), 3.03 - 2.99 (m, 1H), 2.87 (t, J = 7.6Hz, 1H), 2.83 - 2.76 (m, 2H), 2.29 (s, 3H), 2.19 - 2.13 (m, 2H), 1.94 (s, 6H), 1.83 - 1.78 (m, 2H), 1.36 - 1.32 (m, 1H), 0.89 - 0.86 (m, 6H).

[0826] Example 59: (S)-3-((R)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S Preparation of )-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (59a and 59b)

[0827] Referring to the synthesis method of Example 20, 2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to produce:

[0828] 59a, white solid.

[0829] LC-MS: m / z 702.3[M+H] + .

[0830] 1 H-NMR(400MHz,CD3OD)δ8.44(br,1H),7.82(s,1H),7.12-7.02(m,3H),6.78(s,1H),6.61(d ,J=7.6Hz,1H),5.62(t,J=8.0Hz,1H),5.53(t,J=6.8Hz,1H),4.23(t,J=5.6Hz,2H),4.10-4. 06(m,6H),3.37-3.32(m,2H),2.85(t,J=7.2Hz,2H),2.71(d,J=6.8Hz,2H),2.50-2.42(m,2H ),2.16-2.11(m,2H),1.98-1.94(m,5H),1.86(s,3H),1.44-1.38(m,1H),0.95-0.90(m,6H).

[0831] 59b, white solid.

[0832] LC-MS: m / z 702.3[M+H] + .

[0833] 1H-NMR(400MHz,CD3OD)δ8.38(br,1H),7.74(s,1H),7.13-7.04(m,3H),6.88(s,1H),6.64(d,J=7.6Hz,1H), 5.69-5.66(m,1H),5.59(t,J=7.6Hz,1H),4.26(t,J=5.6Hz,2H),4.15(t,J=8.4Hz,4H),4.04(t,J=5.6Hz,2 H),3.45-3.33(m,2H),2.93-2.88(m,1H),2.84-2.76(m,1H),2.66-2.61(m,1H),2.56-2.46(m,2H),2.21-2 .13(m,2H),2.06-2.01(m,2H),1.98-1.91(m,6H),1.70-1.63(m,1H),1.41-1.35(m,1H),0.89-0.87(m,6H).

[0834] Example 60: (S)-3-((R)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S Preparation of )-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (60a and 60b)

[0835] With reference to the synthetic method of Example 20, 2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (4-fluoro-2,6-dimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0836] 60a, white solid.

[0837] LC-MS: m / z 720.2[M+H] + .

[0838] 11H-NMR (400 MHz, CD3OD) δ 8.38 (broad, 1H), 7.83 (singlet, 1H), 6.82 - 6.76 (multiplet, 3H), 6.60 (doublet, J = 7.6 Hz, 1H), 5.63 (doublet, J = 8.0 Hz, 1H), 5.53 (triplet, J = 7.2 Hz, 1H), 4.23 (triplet, J = 5.6 Hz, 2H), 4.12 (triplet, J = 8.0 Hz, 4H), 4.01 (triplet, J = 5.6 Hz, 2H), 3.39 - 3.33 (multiplet, 2H), 2.85 (triplet, J = 7.2 Hz, 2H), 2.73 (doublet, J = 6.8 Hz, 2H), 2.52 - 2.44 (multiplet, 2H), 2.17 - 2.13 (multiplet, 2H), 1.99 - 1.94 (multiplet, 5H), 1.85 (singlet, 3H), 1.47 - 1.38 (multiplet, 1H), 0.96 - 0.91 (multiplet, 6H).

[0839] 60b, white solid.

[0840] LC-MS: m / z 720.2 [M + H] + .

[0841] 1 1H-NMR (400 MHz, CD3OD) δ 8.42 (broad, 1H), 7.73 (singlet, 1H), 6.88 (singlet, 1H), 6.82 (doublet, J = 9.6 Hz, 2H), 6.64 (doublet, J = 8.0 Hz, 1H), 5.69 - 2.65 (multiplet, 1H), 5.59 (triplet, J = 7.6 Hz, 1H), 4.26 (triplet, J = 5.6 Hz, 2H), 4.15 (triplet, J = 8.0 Hz, 4H), 4.05 (triplet, J = 5.2 Hz, 2H), 3.47 - 3.33 (multiplet, 2H), 2.94 - 2.90 (multiplet, 1H), 2.84 - 2.78 (multiplet, 1H), 2.64 - 2.59 (multiplet, 1H), 2.53 - 2.44 (multiplet, 2H), 2.19 - 2.14 (multiplet, 2H), 2.04 - 1.92 (multiplet, 8H), 1.70 - 1.58 (multiplet, 1H), 1.43 - 1.36 (multiplet, 1H), 0.89 (doublet, J = 6.8 Hz, 6H).

[0842] Example 61: Preparation of (S)-3-((R)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (61a and 61b)

[0843] With reference to the synthetic method of Example 20, 2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (mesitylenetrimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0844] 61a, white solid.

[0845] LC-MS: m / z 716.2[M+H] + .

[0846] 1 H-NMR (400MHz, CD3OD) δ8.35(br,1H),7.83(s,1H),6.85(d,J=9.6Hz,2H),6.76(s,1H),6.59(d,J=7.6 Hz,1H),5.64(t,J=8.0Hz,1H),5.53(t,J=6.8Hz,1H),4.22(t,J=5.6Hz,2H),4.11(t,J=8.0Hz,4H),4.0 0(t,J=5.6Hz,2H),3.38-3.34(m,2H),2.85(t,J=7.2Hz,2H),2.73(d,J=6.8Hz,2H),2.52-2.44(m,2H), 2.28(s,3H),2.16-2.10(m,2H),1.97-1.93(m,5H),1.79(s,3H),1.45-1.38(m,1H),0.96-0.91(m,6H).

[0847] 61b, white solid.

[0848] LC-MS: m / z 716.2[M+H]+ .

[0849] 1 H-NMR (400MHz, CD3OD) δ8.36 (s, 1H), 7.74 (s, 1H), 6.88-6.87 (m, 3H), 6.63 (d, J = 8.0Hz, 1H), 5.68-5.64 (m, 1H),5.59(t,J=7.6Hz,1H),4.25(t,J=5.6Hz,2H),4.15(t,J=8.0Hz,4H),4.03(t,J=5.2Hz,2H),3.49-3.33( m,2H),2.91-2.88(m,1H),2.84-2.78(m,1H),2.66-2.61(m,1H),2.56-2.44(m,3H),2.29(s,3H),2.21-2.13 (m,2H),2.05-2.01(m,1H),1.96-1.89(m,6H),1.70-1.62(m,1H),1.43-1.36(m,1H),0.88(d,J=6.4Hz,6H).

[0850] Example 62: Preparation of (S)-3-((R)-2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (62a and 62b)

[0851] With reference to the synthetic method of Example 20, 2-(4-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (4-fluoro-2,6-dimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0852] 62a, white solid.

[0853] LC-MS: m / z 690.5[M+H] + .

[0854] 1 H-NMR(400 MHz, CD3OD) δ 7.79 (s, 1H), 7.11 - 7.09 (m, 3H), 6.68 (d, J = 8.0 Hz, 1H), 5.62 (t, J = 8.0 Hz, 1H), 5.45 (t, J = 5.2 Hz, 1H), 4.24 - 4.22 (m, 2H), 4.07 - 4.03 (m, 2H), 3.33 - 3.29 (m, 2H), 2.94 - 2.92 (m, 2H), 2.85 - 2.77 (m, 6H), 2.69 - 2.62 (m, 2H), 2.19 - 2.16 (m, 2H), 2.01 (s, 3H), 1.94 - 1.82 (m, 2H), 1.75 (s, 3H), 1.54 - 1.50 (m, 1H), 1.34 - 1.31 (m, 1H), 0.89 - 0.82 (m, 6H).

[0855] 62b, white solid.

[0856] LC-MS: m / z 690.5 [M + H] + .

[0857] 1 H-NMR(400 MHz, CD3OD) δ 7.75 (s, 1H), 7.12 - 7.08 (m, 3H), 6.67 (d, J = 8.0 Hz, 1H), 5.63 - 5.60 (m, 2H), 4.30 (t, J = 8.0 Hz, 2H), 4.14 - 4.09 (m, 2H), 3.16 - 3.04 (m, 2H), 2.95 - 2.91 (m, 2H), 2.88 - 2.78 (m, 6H), 2.70 - 2.66 (m, 2H), 2.24 - 2.20 (m, 2H), 2.03 (s, 6H), 1.92 - 1.88 (m, 1H), 1.75 - 1.71 (m, 2H), 1.38 - 1.32 (m, 1H), 0.92 - 0.88 (m, 6H).

[0858] Example 63: Preparation of (S)-3-((R)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(9-(2,6-dimethylphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (63a and 63b)

[0859] Referring to the synthesis method of Example 20, 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid to produce:

[0860] 63a, white solid.

[0861] LC-MS: m / z 704.2[M+H] + .

[0862] 1 H-NMR(400MHz,CD3OD)δ9.17(d,J=7.6Hz,1H),7.81(s,1H),7.12-6.98(m,3H),6.72(s,1H) ,6.60(d,J=8.0Hz,1H),5.76-5.72(m,1H),5.57-5.51(m,1H),4.22(t,J=5.6Hz,2H),4.00( t,J=5.6Hz,2H),3.21-3.17(m,2H),2.90-2.89(m,6H),2.85-2.80(m,2H),2.72-2.62(m,2H ),2.16-2.10(m,2H),2.04-1.89(m,7H),1.75(s,3H),1.47-1.40(m,1H),0.98-0.93(m,6H).

[0863] 63b, white solid.

[0864] LC-MS: m / z 704.2[M+H] + .

[0865] 1H-NMR(400MHz,CD3OD)δ9.18(d,J=8.0Hz,1H),7.85(s,1H),7.14-7.05(m,3H),6.85(s,1H), 6.65(d,J=8.0Hz,1H),5.76(t,J=8.0Hz,1H),5.57-5.51(m,1H),4.31-4.21(m,2H),4.10-4. 00(m,2H),3.23-3.17(m,2H),2.92(s,6H),2.85-2.77(m,2H),2.75-2.60(m,2H),2.19-2.14 (m,2H),2.11-1.90(m,8H),1.80(t,J=7.6Hz,2H),1.36-1.30(m,1H),0.87(d,J=6.4Hz,6H).

[0866] Example 64: (S)-3-((R)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S Preparation of )-3-((S)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-(4-fluoro-2,6-dimethylphenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (64a and 64b)

[0867] With reference to the synthetic method of Example 20, 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (4-fluoro-2,6-dimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0868] 64a, white solid.

[0869] LC-MS: m / z 722.4[M+H] + .

[0870] 1H-NMR (400MHz, CD3OD) δ9.18(d,J=7.6Hz,1H),7.82(s,1H),6.82-6.72(m,3H),6.60(d,J =8.0Hz,1H),5.76-5.72(m,1H),5.56-5.50(m,1H),4.22(t,J=5.6Hz,2H),4.00(t,J=5.6 Hz,2H),3.23-3.17(m,2H),2.90(d,J=3.6Hz,6H),2.84-2.80(m,2H),2.72-2.62(m,2H), 2.16-2.11(m,2H),2.06-1.89(m,7H),1.76(s,3H),1.47-1.40(m,1H),0.98-0.94(m,6H).

[0871] 64b, white solid.

[0872] LC-MS: m / z 722.4[M+H] + .

[0873] 1 H-NMR (400MHz, CD3OD) δ9.19 (d, J = 8.0Hz, 1H), 7.86 (s, 1H), 6.85-6.82 (m, 3H), 6. 64(d,J=7.6Hz,1H),5.76(t,J=8.0Hz,1H),5.56-5.50(m,1H),4.31-4.21(m,2H),4 .10-4.01(m,2H),3.23-3.18(m,2H),2.92(s,6H),2.83-2.60(m,4H),2.20-2.14(m ,2H),2.09-1.90(m,8H),1.84-1.77(m,2H),1.35-1.30(m,1H),0.88-0.86(m,6H).

[0874] Example 65: Preparation of (S)-3-((R)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid and (S)-3-((S)-2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(6-fluoro-9-methyl-3,4-dihydro-2H-benzo[b][1,4]dioxepan-7-yl)propanoic acid (65a and 65b)

[0875] With reference to the synthetic method of Example 20, 2-(5-(3-(dimethylamino)propyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid was substituted for 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid, and (mesitylenetrimethylphenyl)boric acid was substituted for (2,6-dimethylphenyl)boric acid to prepare:

[0876] 65a, white solid.

[0877] LC-MS: m / z 718.4 [M+H] + .

[0878] 1 H-NMR(400MHz,CD3OD)δ9.17(d,J=7.6Hz,1H),7.81(s,1H),6.87(s,1H),6.82(s,1H),6.71(s,1 H),6.58(d,J=7.6Hz,1H),5.74(t,J=8.0Hz,1H),5.56-5.50(m,1H),4.21(t,J=5.6Hz,2H),3.99 (t,J=5.6Hz,2H),3.21-3.16(m,2H),2.89(s,6H),2.84-2.79(m,2H),2.70-2.61(m,2H),2.78(s ,3H),2.19-2.10(m,2H),2.06-1.92(m,7H),1.70(s,3H),1.47-1.40(m,1H),0.98-0.93(m,6H).

[0879] 65b, white solid.

[0880] LC-MS: m / z 718.4 [M+H] + .

[0881] 1H-NMR (400MHz, CD3OD) δ9.18(d,J=7.6Hz,1H),7.85(s,1H),6.89-6.85(m,3H),6.64(d,J=8.0H z,1H),0.76(t,J=8.0Hz,1H),5.56-5.53(m,1H),4.30-4.20(m,2H),4.09-3.99(m,2H),3.25-3 .16(m,2H),2.92(s,6H),2.84-2.77(m,2H),2.73-2.60(m,2H),2.29(s,3H),2.21-2.13(m,2H) ,2.06-1.98(m,2H),1.94(s,6H),1.82-1.78(m,2H),1.35-1.32(m,1H),0.88(d,J=6.4Hz,6H).

[0882] Biological evaluation

[0883] Effect Example 1: In vitro human MAdCAM-1 / α4β7 integrin binding inhibitory activity evaluation experiment

[0884] Recombinant human integrin α4β7 protein (R&D, Catalog No. 5397-A3) was dissolved in carbonate buffer and added to a flat-bottom 96-well ELISA plate at 80 μL per well. Coating was performed overnight at 4°C. Each well was washed three times with 200 μL of wash buffer. 150 μL of assay buffer was added to each well and blocked at 25°C for 1 hour. Compounds were diluted in DMSO starting at 400 μM and serially diluted three-fold over 10 doses. 1 μL of the test compound was transferred to 199 μL of 1X assay buffer. After one wash with wash buffer, 25 μL of the 2X diluted compound and 25 μL of 2X human MAdCAM-1 protein (Acrobiosystems, Catalog No. MAM-H5253) were added to each well. The 96-well plate was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 2 hours. After washing once with wash buffer, add 50 μL of goat anti-human IgG HRP (ABCAM, Catalog No. ab97225) to each well and incubate at 25°C for 1 hour. After washing once with wash buffer, add 30 μL of substrate solution (CST, Catalog No. 7004P4) to each well, centrifuge the 96-well plate at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes. Add 30 μL of stop solution (CST, Catalog No. 7002P4) to each well, centrifuge the 96-well plate at 1000 rpm for 1 minute. Read the OD450 absorbance on the plate using a BMG microscope.

[0885] Inhibition rate calculation

[0886] Average absorbance of compounds at different concentrations

[0887] ABS: Absorbance

[0888] Average absorbance of the positive control for the entire plate

[0889] Average absorbance of negative control for the entire plate

[0890] (2)IC 50 Calculation and compound dose-effect curve

[0891] IC 50 Calculation of inhibition was performed by fitting the inhibition value and the logarithm of compound concentration to nonlinear regression (dose response - variable slope) using Graphpad 8.0.

[0892] In Table 1, the α4β7 integrin inhibitory activity values ​​of the compounds are as follows: A refers to IC 50 ≤30nM; B refers to 30nM <IC 50 ≤100nM; C refers to 100nM <IC 50 ≤500nM; D refers to IC 50 >500 nM; NT means not collected.

[0893] Table 1 Inhibitory activity of the compounds of the present invention on binding to MAdCAM-1 / α4β7 integrin

[0894] Effect Example 2: α4β7 Integrin Cell Adhesion Assay

[0895] 100 μL / well of 1 μg / mL rh-MAdCAM (R&D systems, catalog number 6056-MC) was added to a 96-well PET plate and incubated overnight at 4°C. The plate was washed twice with wash buffer (1X PBS). The plate was sealed at room temperature with 100 μL / well of sealing buffer (1X PBS, 1% BSA). The plate was washed once with PBS. HBSS assay buffer (1X HBSS, 20 mM HEPES, 0.1% BSA, and 1 mM MnCl2) containing the compound was added to the 96-well PET plate at 50 μL / well. The cell index was recorded and background adjusted using an xCELLigence RTCA MP (Agilent, model L-SMP05). 50 μL / well of RPMI8866 cell suspension (ECACC, 95041316) was added to the 96-well PET plate at a final cell concentration of 100,000 cells / well. The plate was plated every 5 minutes using an xCELLigence RTCA MP (Agilent, model L-SMP05). RTCA MP records the cell index.

[0896] Data Analysis

[0897] % inhibition rate = 100 - (Signalcmpd - SignalAve_PC) / (SignalAve_VC - SignalAve_PC) × 100

[0898] Signalcmpd: Cell Index of Compounds

[0899] SignalAve_PC: Cell index of positive control

[0900] SignalAve_VC: Cell index of negative control (0.1% DMSO)

[0901] IC 50 Calculation and compound dose-effect curve

[0902] IC 50 Calculation of inhibition was performed by fitting the inhibition value and the logarithm of compound concentration to nonlinear regression (dose response - variable slope) using Graphpad 8.0.

[0903] In Table 2, the values ​​of the α4β7 integrin cell adhesion inhibitory activity of the compounds are as follows: A refers to IC 50 ≤10nM; B refers to 10nM <IC 50 ≤100nM; C refers to 100nM <IC 50 ≤1000nM; D refers to IC 50 >1000nM.

[0904] Table 2 Inhibitory activity of the compounds of the present invention on α4β7 integrin cell adhesion

[0905] Effect Example 3: Experimental evaluation of compound binding to MAdCAM-1 and α4β7 based on receptor occupancy method

[0906] Whole blood was collected from C57BL / 6 mice (Weitong Lihua (Beijing) Biotechnology Co., Ltd.) using the orbital bleeding method in sodium heparin tubes. Gently mix; 100 μl of whole blood is required for each staining tube. Dilute the test compound from a 10 mM stock solution to 1 mM using DMSO. 2 mL of blood was inoculated with 8 μL of 1 M MnCl2 into a flow cytometer tube. After mixing, 100 μL of blood was removed and added to the compound. The maximum final compound concentration after mixing was 500 nM. Incubate at 4°C for 30 minutes, achieving a final MnCl2 concentration of 4 mM / L. After mixing the 1 M MnCl2 with the blood, 100 μl of blood was removed and added to the compound, mixing thoroughly. Recombinant MAdCAM-1-Fc protein (Acrobiosystems, Cat. No. MAM-H5253) was added to the samples at final concentrations of 500 nM, 125 nM, 31.55 nM, 7.81 nM, 1.9 nM, 0.49 nM, and 0.001 nM, respectively. The samples were incubated at 4°C for 45 minutes. MAdCAM-1-Fc was used at a concentration of 1.2 μg / mL to compete with the test compound binding. The tubes were centrifuged at 1200 rpm for 5 minutes, and the supernatant was discarded. Whole blood 1X BD FACS Lysse (BD, 558049) was added, the tubes were vigorously inverted 8-10 times, and then incubated in a 37°C water bath for 10 minutes. The tubes were centrifuged at 1200 rpm for 5 minutes, and the supernatant was discarded. The cells were then washed once with PBS. The cells were washed with 2 mL of staining buffer (PBS containing 2% fetal bovine serum) and resuspended in 100 μL of staining buffer. The cells were incubated with Fc receptor blockers for 10 minutes, centrifuged at 1200 rpm for 5 minutes, and the supernatant was discarded. The cells were washed once with flow cytometry buffer (PBS solution containing 2% fetal bovine serum). + Antibodies against the α4β7 T cell subset were incubated at 4°C in the dark for 45 minutes. The following antibodies were used: CD4-APC (BD, 553051), CD44-BV605 (BD, 563058), integrin α4-BV421 (BD, 740012), β7-PE (BD, 555945), and AF488 (Invitrogen, A55747). The cells were centrifuged at 1200 rpm for 5 minutes, and the supernatant was discarded. The cells were washed with staining buffer and resuspended in 500 μL of staining buffer for acquisition on a flow cytometer (BD FACS).

[0907] Experimental data processing

[0908] Receptor occupancy = 100 - (( ...

[0909] Graph prism 5.0 software calculates IC 50 value

[0910] In Table 3, the activity values ​​of the compounds on α4β7 receptor occupancy are: A refers to IC 50 ≤50nM; B refers to 50nM <IC 50 ≤200nM; C refers to 200nM <IC 50 ≤500nM; D refers to IC 50 >500nM.

[0911] Table 3 Occupancy activity of the compounds of the present invention on α4β7 receptors

[0912] Effect Example 4: Evaluating the distribution of compounds in vivo based on tissue distribution method

[0913] 1. Preparation of test samples

[0914] Using a graduated stoppered test tube or a quantitative container, use DMSO and PEG400 as solvents (prepared with water for injection or NS). First, add 10% of the total volume of DMSO to dissolve the drug. Once completely dissolved, add 20% of PEG400. Mix thoroughly and finally adjust to the total volume with water for injection. Sonicate until a uniform solution is obtained. Once prepared, label and set aside. Prepare immediately before use, shaking thoroughly before each administration. The preparation method for the remaining compounds is the same.

[0915] 2. Animal Dosing

[0916] The experiments were conducted after the experimental animals (Weitonglihua (Beijing) Biotechnology Co., Ltd.) were acclimated and the animals were fasted (>12 h) but not deprived of water.

[0917] Weigh the animals before dosing and group them according to their weight, with a weight difference of no more than 3g between groups. Serial numbers should be assigned. During dosing, if animals choke on the drug, struggle, or experience inaccurate dosing, or other clinical abnormalities, they should be promptly replaced with a spare animal to ensure experimental accuracy. If animals die or experience abnormal conditions during blood collection after dosing, these should be recorded and the animals will not be replaced.

[0918] 3. Tissue Sample Collection and Processing

[0919] After blood collection, all animals were euthanized without perfusion. The duodenum, ileum, colon and liver tissues were collected from the animals. The duodenum, ileum and colon tissues were cut open to remove the intestinal contents, and then rinsed with pre-cooled saline and dried with filter paper. The tissues were weighed (0.1-0.3 g) and chopped into pieces. Pre-cooled saline was added to the duodenum, ileum, colon and liver at a weight ratio of 1:4. After being homogenized by a tissue homogenizer, they were frozen in a -80°C refrigerator for use in determining the drug concentration in the tissue.

[0920] 4. Data statistics and processing

[0921] Analyst 1.6.3 software or MassLynx V4.2 SCN977 data processing software was used to integrate the analyte and internal standard to determine the peak area. A weighted (1 / x²) least-squares regression was performed, with the analyte concentration as the abscissa and the peak area ratio of the analyte to the internal standard as the ordinate. The resulting linear regression equation constituted the standard curve. The test response of the analyte or the response ratio of the analyte to the internal standard (dependent variable y) was substituted into the regression equation to determine x, which was the plasma concentration of the analyte.

[0922] Mas Studio software (or other alternative software) was used to perform statistical analysis on the blood drug concentration to obtain the drug-time curve of the test product and the T 1 / 2z 、C max 、T max , AUC 0-t , CLz, Vz and other main pharmacokinetic parameters.

[0923] Table 4 PK data in ICR mouse plasma after single oral administration of 10 mg / kg compound (n=3, mean ± SD) BQL: concentration below the detection limit

[0924] Table 5 Average (n=3, mean ± SD) plasma and tissue drug concentrations (μg / L) in ICR mice after a single oral administration of 10 mpk of compound NT: not collected; BQL: concentration below the detection limit a: Sample collected 4 hours after administration; b: Sample collected 8 hours after administration;

[0925] Effect Example 5: Evaluating the distribution of compounds in vivo based on tissue distribution method

[0926] Five 6-week-old female Balb / c donor mice (Wei Tong Li Hua (Beijing) Biotechnology Co., Ltd.) were sacrificed and spleens were harvested from these female Balb / c mice. Spleens were washed in ice-cold sterile sorting buffer (PBS (Gibco, Catalog No. 10010023) containing 2% FBS (Gibco, Catalog No. 10099-141C). Cells were kept on ice for all procedures except the grinding procedure, which was performed at room temperature. Spleens were prepared into a single-cell suspension by wetting a 70 μm filter (FALCON, Catalog No. 352350), placing the spleen in the filter, and triturating with the handle of a syringe. After complete trituration, the filter was rinsed, and the cells were transferred to a centrifuge tube. Centrifuged at 1000 rpm for 5 minutes, the supernatant discarded, and the cells resuspended in PBS.

[0927] 2. Stimulate cells with 30 U / mL rIL-2 and 0.2 μM retinoic acid (Sigma-Aldrich, Cat. No. R2625) and anti-CD3 / CD28 beads. Cells were plated in 12-well plates at a density of 1.5 × 10 6 / mL culture, incubate at 37 ° C, 5% CO2 for 5 days and collect the cells. Prepare mouse T cell culture as day 0. On day 1, observe the cell density. If the proliferation is too dense, transfer the cells to a new 12-well plate for culture. On day 2 and 4, add fresh culture medium while maintaining the concentration of stimulating factors (retinoic acid and IL-2) to expand the cultured cells as needed. Collect cells on day 5 to determine α4β7 + Cell purity was measured and T cells were stained with CFSE (Biolegend, Cat. No. 423801).

[0928] 3. 30 minutes after administration, cells were injected into the tail vein of mice. After culture, CFSE dye (stock concentration is 5mM) working solution with a final concentration of 2.5μM was added to the cultured T cells that highly expressed α4β7 (cell density was adjusted to 10-100×10 6 / mL), incubate in the dark for 20 minutes, then add 1mL of 1640 complete medium, incubate in the dark for 10 minutes, centrifuge at 1000 rpm at room temperature for 5 minutes, and discard the supernatant.

[0929] 4. Use trypan blue staining to determine if the cell viability is greater than 90% and inject it into the tail vein of recipient mice.

[0930] 5. CFSE-stained T cells were injected into 8-week-old female Balb / c recipient mice via tail vein injection, with N=5 per group. Each mouse was injected with 5×10 6 cells.

[0931] 6. One hour after tail vein injection, 7-10 Peyer's patches were collected from recipient mice. After Peyer's patches were removed, they were incubated with 0.5 mg / mL collagenase D at 37°C for 15 minutes. The Peyer's patches were squeezed through a 70 μm cell strainer to prepare a single-cell suspension. The suspension was centrifuged at 1000 rpm for 5 minutes, the supernatant discarded, and the cells were washed once with 2 mL of flow cytometry buffer. The suspension was centrifuged at 1000 rpm at 4°C for 5 minutes, the supernatant discarded, and the cells were resuspended in flow cytometry buffer. A CD3 flow cytometry antibody (Biolegend, Cat. No. 100236) was added, and the suspension was incubated at 4°C in the dark for 30 minutes. The cells were centrifuged at 1000 rpm at 4°C for 5 minutes, the supernatant discarded, and the wash cycle repeated twice. The cells were resuspended in flow cytometry buffer and analyzed using a flow cytometer. Lymphocytes from Peyer's patches were collected using a flow cytometer.

[0932] Experimental data processing:

[0933] Graph Prism 7.0 software processes streaming data

[0934] Positive reference:

[0935] DATK32: Mouse LPAM-1 / α4β7 integrin monoclonal antibody. Manufacturer: MedChemExpress, Cat. No. HY-124290.

[0936] AJM300: Carotegrast Methyl, an oral, small-molecule α4 integrin inhibitor. Manufacturer: MCE, Catalog Number: HY-P99203.

[0937] The results are shown in Figure 1.

Claims

1. A compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, in: Ring A is selected from C6-C 10 Aryl, 6-membered heterocyclic group, 6-membered monocyclic heteroaryl and 9-10-membered cyclic heteroaryl; X1, X2, X3 and X4 are each independently CH or N; Each R1 is independently selected from cyano, hydroxyl, -NR a R b , halogen, -C(O)-R c 、-C(O)-OR c , carbamoyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-membered or 6-membered monocyclic heteroaryl, 9-10-membered cyclic heteroaryl, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6-membered heterocyclic group; Each R2 is independently selected from cyano, hydroxyl, -NR a R b , halogen, =O, -C(O)-R c 、-C(O)-OR c , carbamoyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-membered or 6-membered monocyclic heteroaryl, 9-10-membered cyclic heteroaryl, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6-membered heterocyclic group; or Two R2 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl group; Each R6 is independently selected from cyano, hydroxyl, -NR a R b , halogen, =O, -C(O)-R c 、-C(O)-OR c , carbamoyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 10 Aryl, 5-membered or 6-membered monocyclic heteroaryl, 9-10-membered cyclic heteroaryl, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6-membered heterocyclic group; Each R3 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxy, halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, -NR a R b and -(C1-C6)alkylene-NR a R b , wherein at least one R3 is -(C1-C6)alkylene-NR a R b , the (C1-C6)alkylene group is optionally substituted by one or more substituents selected from C3-C6 cycloalkyl, C1-C6 alkyl, halogen, amino, cyano, nitro, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; R4 is selected from C1-C6 alkyl, -C1-C6 alkylene-C3-C6 cycloalkyl, -C3-C6 cycloalkylene-C1-C6 alkyl and C1-C6 haloalkyl; R5 is hydrogen or C1-C6 alkyl; R a and R b Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; or, R a and R b Together with the N to which it is attached, it forms a 4-6 membered nitrogen-containing heterocyclic group, wherein the 4-6 membered nitrogen-containing heterocyclic group is optionally substituted by one or more substituents selected from C1-C6 alkyl, halogen, amino, cyano, nitro, hydroxyl, =O, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; Each R c Each is independently hydrogen or C1-C6 alkyl; m1 is 0, 1 or 2; m2 is 0, 1, 2, 3 or 4; m3 is 1, 2, 3 or 4; and m4 is 2, 3, 4 or 5.

2. The compound of the general formula (I) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein: Ring A is selected from phenyl, naphthyl, pyridyl, dihydropyridyl, tetrahydropyridyl, pyranyl, tetrahydropyranyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl, preferably phenyl.

3. A compound of the general formula (I) according to any one of claims 1 to 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, which is a compound of the general formula (IIa) or general formula (IIb) or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, in, R1, R2, R3, R4, R5, R6, X1, X2, X3, X4, m1, m2, m3 and m4 are as defined in claim 1.

4. A compound of the general formula (I) according to any one of claims 1 to 3, or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein: Selected from 5. A compound of the general formula (I) according to any one of claims 1 to 4, or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein: Each R1 is independently selected from cyano, hydroxyl, -NH2, halogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl, preferably halogen, C1-C6 haloalkyl and C1-C6 alkyl, more preferably fluorine, methyl and trifluoromethyl; and / or m1 is 0 or 1.

6. A compound of the general formula (I) according to any one of claims 1 to 5, or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein: Each R2 is independently selected from cyano, hydroxyl, -NH2, halogen, =O, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl, preferably =O and C1-C6 alkyl, more preferably =O, methyl and ethyl; or Two R2 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl group, preferably a cyclopropyl group; and / or m2 is 0, 1, 2 or 3.

7. A compound of the general formula (I) according to any one of claims 1 to 6, or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein: Each R3 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxy, halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl, -NR a R b and -(C1-C6)alkylene-NR a R b , wherein at least one R3 is -(C1-C6)alkylene-NR a R b , the (C1-C6) alkylene group is optionally substituted by one or more C3-C6 cycloalkyl groups; R a and R b are each independently hydrogen or C1-C6 alkyl; or, R a and R b Together with the N to which it is attached, it forms a 4-6 membered nitrogen-containing heterocyclic group, wherein the 4-6 membered nitrogen-containing heterocyclic group is optionally substituted with one or more substituents selected from C1-C6 alkyl, halogen and C1-C6 haloalkyl; Preferably, each R3 is independently selected from trifluoromethyl, methoxy, hydroxyl, -(CH2)2-N(CH3)2, -CH2-N(CH3)2, -(CH2)3-N(CH3)2, cyclopropyl, -(CH2)2-azetidinyl, -(CH2)2-N(CH2CH3)2, -(CH2)3-N(CH3)2, -(CH2)2-morpholinyl, Methyl, -N(CH3)2, -(CH2)3-morpholinyl, and difluoromethyl; and / or m3 is 1 or 2.

8. A compound of the general formula (I) according to any one of claims 1 to 7, or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein: R4 is C1-C6 alkyl or -C1-C6 alkylene-C3-C6 cycloalkyl, preferably isobutyl, propyl or -CH2-cyclopropyl.

9. A compound of the general formula (I) according to any one of claims 1 to 8, or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein: R5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, preferably R5 is hydrogen.

10. A compound of the general formula (I) according to any one of claims 1 to 9, or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, wherein: Each R6 is independently selected from cyano, hydroxyl, -NH2, halogen, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl, preferably cyano, halogen, =O, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkyl and C3-C6 cycloalkyl, more preferably cyclopropyl, methyl, chlorine, fluorine, cyano, cyclobutyl, methoxy, ethyl and trifluoromethyl; and / or m4 is 2, 3, or 4.

11. A compound of the general formula (I) according to any one of claims 1 to 10, or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated substance, solvate, mixture thereof, or pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from:

12. A method for preparing a compound represented by the general formula (I) according to any one of claims 1 to 11, comprising the following steps: The compound represented by the general formula (III) and the compound represented by the general formula (IV) undergo condensation reaction in an organic solvent under alkaline conditions, optionally in the presence of a condensation agent, to obtain a compound represented by the general formula (I). Wherein, the condensation reagent is preferably N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate, and the alkaline reagent providing alkaline conditions is preferably N-methylimidazole; wherein Ring A, X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, m1, m2, m3 and m4 are as defined in claim 1.

13. A pharmaceutical composition comprising a compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, mesomorph, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or a pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier or excipient.

14. Use of a compound of formula (I) according to any one of claims 1 to 11 or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or co-crystal, or a pharmaceutical composition according to claim 13 in the preparation of an α4β7 integrin inhibitor.

15. Use of a compound of formula (I) according to any one of claims 1 to 11 or its tautomer, mesomer, racemate, enantiomer, diastereomer, deuterated form, solvate, mixture thereof, or pharmaceutically acceptable salt or cocrystal, or a pharmaceutical composition according to claim 13 in the preparation of a medicament for preventing and / or treating a disease associated with α4β7 integrin activity, wherein the disease is preferably inflammatory bowel disease.

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